Pyrazolo[1,5-a]pyrimidinyl carboxamide compounds and their use in the treatment of medical disorders

ABSTRACT

The invention provides substituted pyrazolo[1,5-a]pyrimidinyl carboxamide and related organic compounds, compositions containing such compounds, medical kits, and methods for using such compounds and compositions to treat medical disorders, e.g., Gaucher disease, Parkinson&#39;s disease, Lewy body disease, dementia, or multiple system atrophy, in a patient. Exemplary substituted pyrazolo[1,5-a]pyrimidinyl carboxamide compounds described herein include 2-heterocyclyl-4-alkyl-pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds and variants thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationSerial No. PCT/US2017/026280, filed Apr. 6, 2017, which claims thebenefit of and priority to U.S. Provisional Patent Application Ser. No.62/318,929, filed Apr. 6, 2016, the contents of each of which are herebyincorporated by reference.

FIELD OF THE INVENTION

The invention provides substituted pyrazolo[1,5-a]pyrimidinylcarboxamide and related organic compounds, compositions containing suchcompounds, medical kits, and methods for using such compounds andcompositions to treat medical disorders in a patient.

BACKGROUND

Gaucher disease is a genetic disorder associated with a deficiency ofthe lysosomal enzyme, glucocerebrosidase. Gaucher disease has beenreported to have an incidence of approximately 1 in 20,000 live birthsin the general population, and it is a common lysosomal storagedisorder. Current treatments for patients suffering from this diseaseinclude enzyme replacement therapy, which tends to be expensive,analgesics for bone pain relief, and medical procedures such as bloodand platelet transfusions, splenectomy, and joint replacement forpatients who experience bone erosion. However, new treatment options areneeded having improved efficacy across a broader range of patientsand/or reduced adverse side effects.

Mutations in the gene encoding glucocerebrosidase are also a risk factorfor Parkinson's disease and diffuse Lewy Body Disease. Parkinson'sdisease is a degenerative disorder of the central nervous systemassociated with death of dopamine-containing cells in a region of themidbrain. Parkinson's disease afflicts millions of people, and theincidence of the disease increases with age. Treatment of Parkinson'sdisease frequently involves use of levodopa and dopamine agonists.However, these drugs can produce significant side effects such ashallucinations, insomnia, nausea, and constipation. Further, patientsoften develop tolerance to these drugs such that the drugs becomeineffective at treating the symptoms of the disease, while sometimesalso producing a movement disorder side effect called dyskinesia.Diffuse Lewy Body disease is a dementia that is sometimes confused withAlzheimer's disease.

Accordingly, the need exists for new therapeutic agents for treatingGaucher disease, Parkinson's disease, and related medical disorders. Thepresent invention addresses this need and provides other relatedadvantages.

SUMMARY

The invention provides substituted pyrazolo[1,5-a]pyrimidinylcarboxamide and related organic compounds, compositions containing suchcompounds, medical kits, and methods for using such compounds andcompositions to treat medical disorders, e.g., Gaucher disease,Parkinson's disease, Lewy body disease, dementia, multiple systematrophy, epilepsy, bipolar disorder, schizophrenia, an anxiety disorder,major depression, polycystic kidney disease, type 2 diabetes, open angleglaucoma, multiple sclerosis, endometriosis, and multiple myeloma, in apatient. Various aspects and embodiments of the invention are describedin further detail below.

Accordingly, one aspect of the invention provides a family ofsubstituted pyrazolo[1,5-a]pyrimidinyl carboxamide and related organiccompounds embraced by Formula I that may be used in the methods,compositions, and kits described herein, wherein Formula I isrepresented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description. Further description ofadditional collections of substituted pyrazolo[1,5-a]pyrimidinylcarboxamide and related organic compounds embraced by Formula I aredescribed in the detailed description.

Another aspect of the invention provides a family of substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide and related organic compoundsembraced by Formula II that may be used in the methods, compositions,and kits described herein, wherein Formula II is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description. Further description ofadditional collections of substituted pyrazolo[1,5-a]pyrimidinylcarboxamide and related organic compounds embraced by Formula II aredescribed in the detailed description

Another aspect of the invention provides a family of substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide and related organic compoundsembraced by Formula III that may be used in the methods, compositions,and kits described herein, wherein Formula III is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description. Further description ofadditional collections of substituted pyrazolo[1,5-a]pyrimidinylcarboxamide and related organic compounds embraced by Formula III aredescribed in the detailed description.

Another aspect of the invention provides a family of substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide and related organic compoundsembraced by Formula IV that may be used in the methods, compositions,and kits described herein, wherein Formula IV is represented by:

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined in the detailed description. Further description ofadditional collections of substituted pyrazolo[1,5-a]pyrimidinylcarboxamide and related organic compounds embraced by Formula IV aredescribed in the detailed description.

Another aspect of the invention provides a pharmaceutical composition,comprising a pharmaceutically acceptable carrier and a substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide or related organic compounddescribed herein, such as a compound of Formula I, I-1, I-A, II, II-A,III, or IV.

Another aspect of the invention provides a method of treating adisorder, e.g., Gaucher disease, Parkinson's disease, Lewy body disease,dementia, multiple system atrophy, epilepsy, bipolar disorder,schizophrenia, an anxiety disorder, major depression, polycystic kidneydisease, type 2 diabetes, open angle glaucoma, multiple sclerosis,endometriosis, and multiple myeloma, in a patient. The method comprisesadministering to a patient in need thereof a therapeutically effectiveamount of a substituted pyrazolo[1,5-a]pyrimidinyl carboxamide orrelated organic compound described herein, such as a compound of FormulaI, I-1, I-A, II, II-A, III, or IV, to treat the disorder, e.g., Gaucherdisease, Parkinson's disease, Lewy body disease, dementia, multiplesystem atrophy, epilepsy, bipolar disorder, schizophrenia, an anxietydisorder, major depression, polycystic kidney disease, type 2 diabetes,open angle glaucoma, multiple sclerosis, or multiple myeloma.

DETAILED DESCRIPTION

The invention provides substituted pyrazolo[1,5-a]pyrimidinylcarboxamide and related organic compounds, compositions containing suchcompounds, medical kits, and methods for using such compounds andcompositions to treat medical disorders in a patient. The practice ofthe present invention employs, unless otherwise indicated, conventionaltechniques of organic chemistry, pharmacology, cell biology, andbiochemistry. Such techniques are explained in the literature, such asin “Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds.,1991-1992); “Current protocols in molecular biology” (F. M. Ausubel etal., eds., 1987, and periodic updates); and “Current protocols inimmunology” (J. E. Coligan et al., eds., 1991), each of which is hereinincorporated by reference in its entirety. Various aspects of theinvention are set forth below in sections; however, aspects of theinvention described in one particular section are not to be limited toany particular section.

I. Definitions

To facilitate an understanding of the present invention, a number ofterms and phrases are defined below.

The terms “a” and “an” as used herein mean “one or more” and include theplural unless the context is inappropriate.

The term “alkyl” as used herein refers to a saturated straight orbranched hydrocarbon, such as a straight or branched group of 1-12,1-10, or 1-6 carbon atoms, referred to herein as C₁-C₁₂alkyl,C₁-C₁₀alkyl, and C₁-C₆alkyl, respectively. Exemplary alkyl groupsinclude, but are not limited to, methyl, ethyl, propyl, isopropyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, butyl,isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl,etc.

The term “alkylene” refers to a diradical of an alkyl group. Anexemplary alkylene group is —CH₂CH₂—.

The term “haloalkyl” refers to an alkyl group that is substituted withat least one halogen. For example, —CH₂F, —CHF₂, —CF₃, —CH₂CF₃, —CF₂CF₃,and the like.

The term “hydroxyalkyl” refers to an alkyl group that is substitutedwith at least one hydroxyl group. For example, exemplary hydroxyalkylgroups include —CH₂OH, —C(H)(OH)CH₃, and the like. In certainembodiments, the hydroxyalkyl is an alkyl group that is substituted withjust one hydroxyl group.

The term “cyanoalkyl” refers to an alkyl group that is substituted withone cyano group.

The term “heteroalkyl” as used herein refers to an “alkyl” group inwhich at least one carbon atom has been replaced with a heteroatom(e.g., an O, N, or S atom). The heteroalkyl may be, for example, an—O—C₁-C₁₀alkyl group, an —C₁-C₆alkylene-O—C₁-C₆alkyl group, or a C₁-C₆alkylene-OH group. In certain embodiments, the “heteroalkyl” may be 2-8membered heteroalkyl, indicating that the heteroalkyl contains from 2 to8 atoms selected from the group consisting of carbon, oxygen, nitrogen,and sulfur. In yet other embodiments, the heteroalkyl may be a 2-6membered, 4-8 membered, or a 5-8 membered heteroalkyl group (which maycontain for example 1 or 2 heteroatoms selected from the group oxygenand nitrogen). One type of heteroalkyl group is an “alkoxyl” group.

The term “alkenyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon double bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C₂-C₁₂alkenyl, C₂-C₁₀alkenyl, and C₂-C₆alkenyl,respectively. Exemplary alkenyl groups include vinyl, allyl, butenyl,pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, and the like.

The term “alkynyl” as used herein refers to an unsaturated straight orbranched hydrocarbon having at least one carbon-carbon triple bond, suchas a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms,referred to herein as C₂-C₁₂alkynyl, C₂-C₁₀alkynyl, and C₂-C₆alkynyl,respectively. Exemplary alkynyl groups include ethynyl, prop-1-yn-1-yl,and but-1-yn-1-yl.

The term “cycloalkyl” refers to a monovalent saturated cyclic, bicyclic,bridged cyclic (e.g., adamantyl), or spirocyclic hydrocarbon group of3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as“C₄₋₈cycloalkyl,” derived from a cycloalkane. Exemplary cycloalkylgroups include, but are not limited to, cyclohexanes, cyclopentanes,cyclobutanes and cyclopropanes. Unless specified otherwise, cycloalkylgroups are optionally substituted at one or more ring positions with,for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl,amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate,carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl,heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate,phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl orthiocarbonyl. In certain embodiments, the cycloalkyl group is notsubstituted, i.e., it is unsubstituted.

The term “cycloalkylene” refers to a diradical of an cycloalkyl group.An exemplary cycloalkylene group is

The term “cycloalkenyl” as used herein refers to a monovalentunsaturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl)hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons containing onecarbon-carbon double bond, referred to herein, e.g., as“C₄₋₈cycloalkenyl,” derived from a cycloalkane. Exemplary cycloalkenylgroups include, but are not limited to, cyclohexenes, cyclopentenes, andcyclobutenes. Unless specified otherwise, cycloalkenyl groups areoptionally substituted at one or more ring positions with, for example,alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl,arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl,ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl,hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato,sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certainembodiments, the cycloalkenyl group is not substituted, i.e., it isunsubstituted.

The term “aryl” is art-recognized and refers to a carbocyclic aromaticgroup. Representative aryl groups include phenyl, naphthyl, anthracenyl,and the like. The term “aryl” includes polycyclic ring systems havingtwo or more carbocyclic rings in which two or more carbons are common totwo adjoining rings (the rings are “fused rings”) wherein at least oneof the rings is aromatic and, e.g., the other ring(s) may becycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls. Unlessspecified otherwise, the aromatic ring may be substituted at one or morering positions with, for example, halogen, azide, alkyl, aralkyl,alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl,carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide,ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties,—CF₃, —CN, or the like. In certain embodiments, the aromatic ring issubstituted at one or more ring positions with halogen, alkyl, hydroxyl,or alkoxyl. In certain other embodiments, the aromatic ring is notsubstituted, i.e., it is unsubstituted. In certain embodiments, the arylgroup is a 6-10 membered ring structure.

The term “aralkyl” refers to an alkyl group substituted with an arylgroup.

The term “bicyclic carbocyclyl that is partially unsaturated” refers toa bicyclic carbocyclic group containing at least one double bond betweenring atoms and at least one ring in the bicyclic carbocyclic group isnot aromatic. Representative examples of a bicyclic carbocyclyl that ispartially unsaturated include, for example:

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl” and “heterocyclic group” are art-recognized andrefer to saturated, partially unsaturated, or aromatic 3- to 10-memberedring structures, alternatively 3- to 7-membered rings, whose ringstructures include one to four heteroatoms, such as nitrogen, oxygen,and sulfur. The number of ring atoms in the heterocyclyl group can bespecified using C_(x)-C_(x) nomenclature where x is an integerspecifying the number of ring atoms. For example, a C₃-C₇heterocyclylgroup refers to a saturated or partially unsaturated 3- to 7-memberedring structure containing one to four heteroatoms, such as nitrogen,oxygen, and sulfur. The designation “C₃-C₇” indicates that theheterocyclic ring contains a total of from 3 to 7 ring atoms, inclusiveof any heteroatoms that occupy a ring atom position. One example of aC₃heterocyclyl is aziridinyl. Heterocycles may also be mono-, bi-, orother multi-cyclic ring systems. A heterocycle may be fused to one ormore aryl, partially unsaturated, or saturated rings. Heterocyclylgroups include, for example, biotinyl, chromenyl, dihydrofuryl,dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl,homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl,isooxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl,piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl,pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl,tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl,tetrahydroquinolyl, thiazolidinyl, thiolanyl, thiomorpholinyl,thiopyranyl, xanthenyl, lactones, lactams such as azetidinones andpyrrolidinones, sultams, sultones, and the like. Unless specifiedotherwise, the heterocyclic ring is optionally substituted at one ormore positions with substituents such as alkanoyl, alkoxy, alkyl,alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido,carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl,halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone,nitro, oxo, phosphate, phosphonato, phosphinato, sulfate, sulfide,sulfonamido, sulfonyl and thiocarbonyl. In certain embodiments, theheterocyclyl group is not substituted, i.e., it is unsubstituted.

The term “bicyclic heterocyclyl” refers to a heterocyclyl group thatcontains two rings that are fused together. Representative examples of abicyclic heterocyclyl include, for example:

In certain embodiments, the bicyclic heterocyclyl is an carbocyclic ringfused to partially unsaturated heterocyclic ring, that together form abicyclic ring structure having 8-10 ring atoms (e.g., where there are 1,2, 3, or 4 heteroatoms selected from the group consisting of nitrogen,oxygen, and sulfur).

The term “oxoheterocyclyl” refers to a heterocyclyl group that issubstituted with at least one oxo group (i.e., ═O). In certainembodiments, the oxoheterocyclyl is substituted with 1 or 2 oxo groups.In certain embodiments, the oxoheterocyclyl is a 5-6 membered saturatedheterocyclyl substituted with 1 or 2 oxo groups.

The term “heterocycloalkyl” is art-recognized and refers to a saturatedheterocyclyl group as defined above. In certain embodiments, the“heterocycloalkyl” is a 3- to 10-membered ring structures, alternativelya 3- to 7-membered rings, whose ring structures include one to fourheteroatoms, such as nitrogen, oxygen, and sulfur.

The term “heterocycloalkylene” refers to a diradical of aheterocycloalkyl group. An exemplary heterocycloalkylene group is

The heterocycloalkylene may contain, for example, 3-6 ring atom (i.e., a3-6 membered heterocycloalkylene). In certain embodiments, theheterocycloalkylene is a 3-6 membered heterocycloalkylene containing 1,2, or 3 three heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur.

The term “heteroaryl” is art-recognized and refers to aromatic groupsthat include at least one ring heteroatom. In certain instances, aheteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representativeexamples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl,imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl,pyrazinyl, pyridazinyl and pyrimidinyl, and the like. Unless specifiedotherwise, the heteroaryl ring may be substituted at one or more ringpositions with, for example, halogen, azide, alkyl, aralkyl, alkenyl,alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino,amido, carboxylic acid, —C(O)alkyl, —CO₂alkyl, carbonyl, carboxyl,alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester,heterocyclyl, aryl or heteroaryl moieties, —CF₃, —CN, or the like. Theterm “heteroaryl” also includes polycyclic ring systems having two ormore rings in which two or more carbons are common to two adjoiningrings (the rings are “fused rings”) wherein at least one of the rings isheteroaromatic, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, and/or aryls. In certain embodiments, theheteroaryl ring is substituted at one or more ring positions withhalogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, theheteroaryl ring is not substituted, i.e., it is unsubstituted. Incertain embodiments, the heteroaryl group is a 5- to 10-membered ringstructure, alternatively a 5- to 6-membered ring structure, whose ringstructure includes 1, 2, 3, or 4 heteroatoms, such as nitrogen, oxygen,and sulfur.

The term “heteroaralkyl” refers to an alkyl group substituted with aheteroaryl group.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety represented by thegeneral formula —N(R⁵⁰)(R⁵¹), wherein R⁵⁰ and R⁵¹ each independentlyrepresent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl,aralkyl, or —(CH₂)_(m)—R⁶¹; or R⁵⁰ and R⁵¹, taken together with the Natom to which they are attached complete a heterocycle having from 4 to8 atoms in the ring structure; R⁶¹ represents an aryl, a cycloalkyl, acycloalkenyl, a heterocycle or a polycycle; and m is zero or an integerin the range of 1 to 8. In certain embodiments, R⁵⁰ and R⁵¹ eachindependently represent hydrogen, alkyl, alkenyl, or —(CH₂)_(m)—R⁶¹.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,—O—(CH₂)_(m)—R₆₁, where m and R₆₁ are described above. The term“haloalkoxyl” refers to an alkoxyl group that is substituted with atleast one halogen. For example, —O—CH₂F, —O—CHF₂, —O—CF₃, and the like.In certain embodiments, the haloalkoxyl is an alkoxyl group that issubstituted with at least one fluoro group. In certain embodiments, thehaloalkoxyl is an alkoxyl group that is substituted with from 1-6, 1-5,1-4, 2-4, or 3 fluoro groups.

The term “carbamate” as used herein refers to a radical of the form—R_(g)OC(O)N(R_(h))—, —R_(g)OC(O)N(R_(h))R_(i-), or —OC(O)NR_(h)R_(i),wherein R_(g), R_(h) and R_(i) are each independently alkoxy, aryloxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carboxy, cyano,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydroxyl, ketone, nitro, sulfide, sulfonyl, orsulfonamide. Exemplary carbamates include arylcarbamates and heteroarylcarbamates, e.g., wherein at least one of R_(g), R_(h) and R_(i) areindependently aryl or heteroaryl, such as phenyl and pyridinyl.

The term “carbonyl” as used herein refers to the radical —C(O)—.

The term “carboxamido” as used herein refers to the radical —C(O)NRR′,where R and R′ may be the same or different. R and R′ may beindependently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl,heteroaryl, or heterocyclyl.

The term “carboxy” as used herein refers to the radical —COOH or itscorresponding salts, e.g. —COONa, etc.

The term “amide” or “amido” as used herein refers to a radical of theform —R_(a)C(O)N(R_(b))—, —R_(a)C(O)N(R_(b))R_(c)—, —C(O)NR_(b)R_(c), or—C(O)NH₂, wherein R_(a), R_(b) and R_(c) are each independently alkoxy,alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate,cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl,heterocyclyl, hydrogen, hydroxyl, ketone, or nitro. The amide can beattached to another group through the carbon, the nitrogen, R_(b),R_(c), or R_(a). The amide also may be cyclic, for example R_(b) andR_(c), R_(a) and R_(b), or R_(a) and R_(c) may be joined to form a 3- to12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-memberedring.

The term “amidino” as used herein refers to a radical of the form—C(═NR)NR′R″ where R, R′, and R″ are each independently alkyl, alkenyl,alkynyl, amide, aryl, arylalkyl, cyano, cycloalkyl, haloalkyl,heteroaryl, heterocyclyl, hydroxyl, ketone, or nitro.

The term “alkanoyl” as used herein refers to a radical —O—CO-alkyl.

The term “oxo” is art-recognized and refers to a “═O” substituent. Forexample, a cyclopentane substituted with an oxo group is cyclopentanone.

The term “sulfonamide” or “sulfonamido” as used herein refers to aradical having the structure —N(R_(r))—S(O)₂—R_(s)— or—S(O)₂—N(R_(r))R_(s), where R_(r), and R_(s) can be, for example,hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl. Exemplarysulfonamides include alkylsulfonamides (e.g., where R_(s) is alkyl),arylsulfonamides (e.g., where R_(s) is aryl), cycloalkyl sulfonamides(e.g., where R_(s) is cycloalkyl), and heterocyclyl sulfonamides (e.g.,where R_(s) is heterocyclyl), etc.

The term “sulfonyl” as used herein refers to a radical having thestructure R_(u)SO₂—, where R_(u) can be alkyl, aryl, cycloalkyl, andheterocyclyl, e.g., alkylsulfonyl. The term “alkylsulfonyl” as usedherein refers to an alkyl group attached to a sulfonyl group.

The symbol “

” indicates a point of attachment.

The compounds of the disclosure may contain one or more chiral centersand/or double bonds and, therefore, exist as stereoisomers, such asgeometric isomers, enantiomers or diastereomers. The term“stereoisomers” when used herein consist of all geometric isomers,enantiomers or diastereomers. These compounds may be designated by thesymbols “R” or “S,” depending on the configuration of substituentsaround the stereogenic carbon atom. The present invention encompassesvarious stereoisomers of these compounds and mixtures thereof.Stereoisomers include enantiomers and diastereomers. Mixtures ofenantiomers or diastereomers may be designated “(±)” in nomenclature,but the skilled artisan will recognize that a structure may denote achiral center implicitly. It is understood that graphical depictions ofchemical structures, e.g., generic chemical structures, encompass allstereoisomeric forms of the specified compounds, unless indicatedotherwise.

Individual stereoisomers of compounds of the present invention can beprepared synthetically from commercially available starting materialsthat contain asymmetric or stereogenic centers, or by preparation ofracemic mixtures followed by resolution methods well known to those ofordinary skill in the art. These methods of resolution are exemplifiedby (1) attachment of a mixture of enantiomers to a chiral auxiliary,separation of the resulting mixture of diastereomers byrecrystallization or chromatography and liberation of the optically pureproduct from the auxiliary, (2) salt formation employing an opticallyactive resolving agent, or (3) direct separation of the mixture ofoptical enantiomers on chiral chromatographic columns. Stereoisomericmixtures can also be resolved into their component stereoisomers bywell-known methods, such as chiral-phase gas chromatography,chiral-phase high performance liquid chromatography, crystallizing thecompound as a chiral salt complex, or crystallizing the compound in achiral solvent. Further, enantiomers can be separated usingsupercritical fluid chromatographic (SFC) techniques described in theliterature. Still further, stereoisomers can be obtained fromstereomerically-pure intermediates, reagents, and catalysts bywell-known asymmetric synthetic methods.

Geometric isomers can also exist in the compounds of the presentinvention. The symbol

denotes a bond that may be a single, double or triple bond as describedherein. The present invention encompasses the various geometric isomersand mixtures thereof resulting from the arrangement of substituentsaround a carbon-carbon double bond or arrangement of substituents arounda carbocyclic ring. Substituents around a carbon-carbon double bond aredesignated as being in the “Z” or “E” configuration wherein the terms“Z” and “E” are used in accordance with IUPAC standards. Unlessotherwise specified, structures depicting double bonds encompass boththe “E” and “Z” isomers.

Substituents around a carbon-carbon double bond alternatively can bereferred to as “cis” or “trans,” where “cis” represents substituents onthe same side of the double bond and “trans” represents substituents onopposite sides of the double bond. The arrangement of substituentsaround a carbocyclic ring are designated as “cis” or “trans.” The term“cis” represents substituents on the same side of the plane of the ringand the term “trans” represents substituents on opposite sides of theplane of the ring. Mixtures of compounds wherein the substituents aredisposed on both the same and opposite sides of plane of the ring aredesignated “cis/trans.”

The invention also embraces isotopically labeled compounds of theinvention which are identical to those recited herein, except that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively.

Certain isotopically-labeled disclosed compounds (e.g., those labeledwith ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labeled compounds of the invention cangenerally be prepared by following procedures analogous to thosedisclosed in, e.g., the Examples herein by substituting an isotopicallylabeled reagent for a non-isotopically labeled reagent.

As used herein, the terms “subject” and “patient” refer to organisms tobe treated by the methods of the present invention. Such organisms arepreferably mammals (e.g., murines, simians, equines, bovines, porcines,canines, felines, and the like), and more preferably humans.

As used herein, the term “effective amount” refers to the amount of acompound (e.g., a compound of the present invention) sufficient toeffect beneficial or desired results. An effective amount can beadministered in one or more administrations, applications or dosages andis not intended to be limited to a particular formulation oradministration route. As used herein, the term “treating” includes anyeffect, e.g., lessening, reducing, modulating, ameliorating oreliminating, that results in the improvement of the condition, disease,disorder, and the like, or ameliorating a symptom thereof.

As used herein, the term “pharmaceutical composition” refers to thecombination of an active agent with a carrier, inert or active, makingthe composition especially suitable for diagnostic or therapeutic use invivo or ex vivo.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions (e.g., such as an oil/wateror water/oil emulsions), and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Forexamples of carriers, stabilizers and adjuvants, see Martin, Remington'sPharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, Pa. [1975].

As used herein, the term “pharmaceutically acceptable salt” refers toany pharmaceutically acceptable salt (e.g., acid or base) of a compoundof the present invention which, upon administration to a subject, iscapable of providing a compound of this invention or an activemetabolite or residue thereof. As is known to those of skill in the art,“salts” of the compounds of the present invention may be derived frominorganic or organic acids and bases. Examples of acids include, but arenot limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric,fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic,toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic,ethanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic,benzenesulfonic acid, and the like. Other acids, such as oxalic, whilenot in themselves pharmaceutically acceptable, may be employed in thepreparation of salts useful as intermediates in obtaining the compoundsof the invention and their pharmaceutically acceptable acid additionsalts.

Examples of bases include, but are not limited to, alkali metal (e.g.,sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides,ammonia, and compounds of formula NW₄ ⁺, wherein W is C₁₋₄ alkyl, andthe like.

Examples of salts include, but are not limited to: acetate, adipate,alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,citrate, camphorate, camphorsulfonate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, fumarate, flucoheptanoate,glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate,pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate,succinate, tartrate, thiocyanate, tosylate, undecanoate, and the like.Other examples of salts include anions of the compounds of the presentinvention compounded with a suitable cation such as Na⁺, NH₄ ⁺, and NW₄⁺ (wherein W is a C₁₋₄ alkyl group), and the like.

For therapeutic use, salts of the compounds of the present invention arecontemplated as being pharmaceutically acceptable. However, salts ofacids and bases that are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound.

Abbreviations as used herein includeO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU); diisopropylethylamine (DIPEA);dimethylformamide (DMF); methylene chloride (DCM); tert-butoxycarbonyl(Boc); tetrahydrofuran (THF); trifluoroacetic acid (TFA);N-methylmorpholine (NMM); triethylamine (TEA); Boc anhydride ((Boc)₂O);dimethylsulfoxide (DMSO); diisopropylethylamine (DIEA); ethyl acetate(EA); flash column chromatography (FCC); and supercritical fluidchromatography (SFC).

Throughout the description, where compositions and kits are described ashaving, including, or comprising specific components, or where processesand methods are described as having, including, or comprising specificsteps, it is contemplated that, additionally, there are compositions andkits of the present invention that consist essentially of, or consistof, the recited components, and that there are processes and methodsaccording to the present invention that consist essentially of, orconsist of, the recited processing steps.

As a general matter, compositions specifying a percentage are by weightunless otherwise specified. Further, if a variable is not accompanied bya definition, then the previous definition of the variable controls.

II. Substituted Pyrazolo[1,5-a]Pyrimidinyl Carboxamide and RelatedOrganic Compounds

One aspect of the invention provides substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide and related organic compounds.The substituted pyrazolo[1,5-a]pyrimidinyl carboxamide and relatedorganic compounds are contemplated to be useful in the methods,compositions, and kits described herein. In certain embodiments, thesubstituted pyrazolo[1,5-a]pyrimidinyl carboxamide or related organiccompound is a compound embraced by Formula I:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ and R² each represent independently for each occurrence        hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄        cyanoalkyl, C₁₋₄ alkoxyl, C₁₋₄ haloalkoxyl, cyclopropyl, cyano,        halogen, hydroxyl, —N(R⁴)₂, —O—(C₁₋₄ alkylene)-C₁₋₆ alkoxyl, or        —(C₁₋₄ alkylene)-(2-6 membered heteroalkyl optionally        substituted by one or more halogen);    -   R³ represents independently for each occurrence hydrogen, C₁₋₆        alkyl, or C₃₋₆ cycloalkyl;    -   R⁴ represents independently for each occurrence hydrogen, C₁₋₄        alkyl, cyclopropyl, or —C(O)R³;    -   R⁵ represents independently for each occurrence C₁₋₄ alkyl or        C₃₋₆ cycloalkyl;    -   R⁶ represents independently for each occurrence C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxyl, cyano, halogen, hydroxyl, or —N(R⁴)₂;    -   R⁷ represents independently for each occurrence halogen,        hydroxyl, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₁₋₄        haloalkoxyl, C₃₋₆ cycloalkyl, —O—(C₃₋₆ cycloalkyl), —O—(C₁₋₆        alkylene)-C₁₋₆ alkoxyl, —(C₁₋₆ alkylene)-CN, —N(R⁴)₂,        —C(O)N(R⁴)₂, or heteroaryl;    -   R⁸ is a bond or C₁₋₆ alkylene;    -   R⁹ is hydrogen or C₁₋₆ alkyl;    -   X¹-A¹ is one of the following:        -   X¹ is a carbonyl-containing linker selected from            —C(O)N(H)(C₁₋₆ haloalkylene)-ψ, —C(O)N(H)(C₁₋₆ alkylene            substituted with C₁₋₄ alkoxyl or C₃₋₆ cycloalkyl)-ψ,            —C(O)N(H)(C₃₋₆ cycloalkylene)-ψ, —C(O)N(H)(3-6 membered            heterocycloalkylene)-ψ, and —C(O)-(3-6 membered            heterocycloalkylene containing at least one ring —N(H)—            group)-ψ, where ψ is a bond to A¹; wherein A¹ is one of the            following:            -   (i) a cyclic group selected from a 3-14 membered                saturated carbocyclyl, a 5-14 membered partially                unsaturated carbocyclyl, a 3-16 membered heterocyclyl,                or phenyl; each of which is substituted by 0, 1, or 2                occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²;                or            -   (ii) C₁₋₈ alkyl or C₂₋₆ alkynyl;        -   X¹ is —C(O)N(H)(C₁₋₆ alkylene)-ψ, where ψ is a bond to A¹,            and A¹ is (i) a cyclic group selected from a 5-14 membered            partially unsaturated carbocyclyl, a 3-16 membered            heterocyclyl, or phenyl; each of which is substituted by 0,            1, or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of            Y²; or (ii) C₂₋₆ alkynyl;        -   X¹ is —C(O)N(H)-ψ, where ψ is a bond to A¹, and A¹ is cyclic            group selected from a 5-14 membered partially unsaturated            carbocyclyl, a 3-16 membered heterocyclyl, or phenyl; each            of which is substituted by 0, 1, or 2 occurrences of Y¹ and            0, 1, 2, or 3 occurrences of Y²; and provided that R¹ is not            hydrogen;        -   X¹ is —C(O)N(H)-ψ, where ψ is a bond to A¹, and A¹ is C₂₋₆            alkynyl;        -   X¹ is —C(O)N(H)(C₁₋₆ alkylene)-ψ or —C(O)N(H)-ψ, where ψ is            a bond to A¹, and A¹ is a 6-14 membered saturated            carbocyclyl substituted by 0, 1, or 2 occurrences of Y¹ and            0, 1, 2, or 3 occurrences of Y²; provided that A² is not a            5-membered heteroaryl optionally substituted by 1, 2, or 3            occurrences of R⁷;        -   X¹ is —C(O)N(H)(C₁₋₆ alkylene)-ψ or —C(O)N(H)-ψ, where ψ is            a bond to A¹, and A¹ is a 6-14 membered saturated            spirocyclic carbocyclyl substituted by 0, 1, or 2            occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²;        -   X¹ is —C(O)N(H)C(C₁₋₆ alkyl)₂-R⁸-ψ or —C(O)N(H)C(C₁₋₆            alkyl)(R⁹)—R⁸-ψ, where ψ is a bond to A¹, and A¹ is a 3-5            membered saturated carbocyclyl substituted by 0, 1, or 2            occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²; or        -   X¹ is —C(O)N(H)C(O)-ψ or —C(O)N(H)C(O)(C₁₋₆ alkylene)-ψ,            where ψ is a bond to A¹; and A¹ is (i) a cyclic group            selected from a 3-14 membered saturated carbocyclyl, a 5-14            membered partially unsaturated carbocyclyl, a 3-16 membered            heterocyclyl, or phenyl; each of which is substituted by 0,            1, or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of            Y²; or (ii) C₁₋₈ alkyl or C₂₋₆ alkynyl;    -   A² is one of the following:        -   phenyl substituted by 1, 2, or 3 occurrences of R⁷;        -   a cyclic group selected from a 3-12 membered heterocyclyl,            4-12 membered oxoheterocyclyl, or 4-10 membered cycloalkyl;            each of which is optionally substituted by 1, 2, or 3            occurrences of R⁷; or        -   —N(R⁴)(3-10 membered heterocyclyl, C₃₋₁₀ cycloalkyl, or            phenyl, each optionally substituted by 1, 2, or 3            occurrences of R⁶) or —O-(3-10 membered heterocyclyl, C₃₋₁₀            cycloalkyl, or phenyl, each optionally substituted by 1, 2,            or 3 occurrences of R⁶);    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6-10            membered aryl, a 3-10 membered heterocyclyl, or C₃₋₆            halocycloalkyl;        -   3-10 membered heterocyclyl, 6-10 membered aryl, C₃₋₇            cycloalkyl, —O—C₃₋₆ cycloalkyl, —O-(3-6 membered            heterocyclyl), —O-(6-10 membered aryl), or —O—(C₂₋₆            alkynyl); or        -   C₂₋₆ alkynyl, —C≡C—(C₁₋₆ alkylene)-OR⁴, —C≡C—(C₁₋₆            alkylene)-N(R³)₂, —(C₂₋₄ alkynylene)-(5-6 membered            heteroaryl), or C₂₋₆ alkenyl;    -   Y² represents, independently for each occurrence, C₁₋₆ alkyl,        C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,        hydroxyl, C₁₋₆ alkoxyl, —O—(C₁₋₈ haloalkyl), cyano, azido,        —N(R³)₂, —(C₁₋₆ alkylene)-(5-6 membered heterocyclyl), —(C₁₋₆        alkylene)-CO₂R³, —CO₂R³, —C(O)R⁵, —S(O)₂R⁵, —C(O)N(R⁵)₂,        —C(O)N(R³)₂, or C₁₋₆ haloalkyl-substituted C₃₋₆ cycloalkyl; and    -   n is 1, 2, or 3;    -   provided that when A² is a 5-6 membered heterocycloalkyl and X¹        is —C(O)N(H)-ψ, then A¹ is not -phenyl-(C₁₋₆ alkyl).

Definitions of the variables in Formula I above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where X¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-ψ, R¹ and R² eachrepresent independently for each occurrence hydrogen or C₁₋₄ alkyl, andA² is phenyl substituted by 1 or 2 R⁷.

Accordingly, in certain embodiments, X¹ is —C(O)N(H)(C₁₋₆haloalkylene)-ψ. In certain embodiments, X¹ is —C(O)N(H)C(H)(CF₃)-ψ. Incertain embodiments, X¹ is —C(O)N(H)(C₁₋₆ alkylene)-ψ. In certainembodiments, X¹ is —C(O)N(H)(C(CH₃)₂)-ψ or —C(O)N(H)(C(H)(CH₃))-ψ. Incertain embodiments, X¹ is —C(O)N(H)(C₁₋₆ alkylene substituted with C₁₋₄alkoxyl)-ψ. In certain embodiments, X¹ is —C(O)N(H)(C₁₋₆ alkylenesubstituted with C₃₋₆ cycloalkyl)-ψ. In certain embodiments, X¹ is—C(O)N(H)(C₃₋₆ cycloalkylene)-ψ. In certain embodiments, X¹ is—C(O)N(H)(3-6 membered heterocycloalkylene)-ψ. In certain embodiments,X¹ is —C(O)N(H)-ψ.

In certain embodiments, A² is phenyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,hydroxyl, and —N(R⁴)₂. In certain embodiments, A² is phenyl substitutedby 1, 2, or 3 substituents independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl,cyano, and halogen, wherein there is at least one substituent at ameta-position on the phenyl group. In certain embodiments, A² is phenylsubstituted at one meta-position by C₁₋₄ alkoxyl, cyano, or halogen, andoptionally substituted elsewhere on the phenyl group by C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, or halogen. In certainembodiments, A² is phenyl substituted by C₁₋₄ alkoxyl, cyano, orhalogen. In certain embodiments, A² is phenyl substituted at onemeta-position by C₁₋₄ alkoxyl, cyano, or halogen.

In certain embodiments, A² is a 5-12 membered heterocyclyl optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂. In certainembodiments, A² is a 5-6 membered heteroaryl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano,halogen, hydroxyl, and —N(R⁴)₂. In certain embodiments, A² is a 5-6membered heteroaryl selected from the group consisting of pyridinyl,pyrimidinyl, pyrazinyl, furanyl, pyrrolyl, thiophenyl, imidazolyl,oxazolyl, isoxazolyl, isothiazolyl, and thiazolyl, each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl,C₃₋₅ cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂. In certainembodiments, A² is a 5-6 membered heteroaryl selected from the groupconsisting of pyridinyl, pyrimidinyl, pyrazinyl, furanyl, pyrrolyl,thiophenyl, oxazolyl, isoxazolyl, and thiazolyl, each of which isoptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl,C₃₋₅ cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂. In certainembodiments, A² is pyridinyl optionally substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,hydroxyl, and —N(R⁴)₂. In certain embodiments, A² is 3-pyridinyloptionally substituted by 1 or 2 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl,C₃₋₅ cycloalkyl, cyano, and halogen.

In certain embodiments, A² is a 5-6 membered heteroaryl selected fromthe group consisting of pyridinyl, pyrimidinyl, pyrazinyl, furanyl,pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,pyrazolyl, and oxadiazolyl each of which is optionally substituted by 1,2, or 3 substituents independently selected from the group consisting ofC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano,halogen, hydroxyl, and —N(R⁴)₂.

In certain embodiments, A² is a bicyclic heteroaryl selected from thegroup consisting of benzimidazolyl, benzoxazolyl, benzodioxolyl, andbenzothiazolyl, each of which is optionally substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,hydroxyl, and —N(R⁴)₂.

In certain embodiments, A² is a 5-6 membered heterocycloalkyl optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂. In certainembodiments, A² is a 5-6 membered heterocycloalkyl selected from thegroup consisting of morpholinyl, piperidinyl, pyrrolidinyl,tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂.

In certain embodiments, A² is a 4-12 membered oxoheterocyclyl optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂. In certainembodiments, A² is a 5-6 membered oxoheterocyclyl optionally substitutedby 1, 2, or 3 substituents independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl,cyano, halogen, hydroxyl, and —N(R⁴)₂. In certain embodiments, A² is a5-6 membered oxoheterocyclyl selected from the group consisting ofoxoimidazolidinyl, oxotetrahydropyrimidinyl, oxooxazolidinyl,oxopyrrolidinyl, and oxotetrahydrofuranyl, each of which is optionallysubstituted by 1, 2, or 3 substituents selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl,cyano, halogen, hydroxyl, and —N(R⁴)₂. In certain embodiments, A² is a5-6 membered oxoheterocyclyl selected from the group consisting ofoxoimidazolidinyl, oxotetrahydropyrimidin-1(2H)-yl, oxooxazolidinyl, andoxopyrrolidinyl, each of which is optionally substituted by 1, 2, or 3substituents selected from the group consisting of C₁₋₄ alkyl and C₁₋₄haloalkyl.

In certain embodiments, A² is a 5-10 membered cycloalkyl optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂. In certainembodiments, A² is a 5-6 membered cycloalkyl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano,halogen, hydroxyl, and —N(R⁴)₂.

In certain embodiments, A² is —N(R⁴)(3-10 membered heterocyclyl, C₃₋₁₀cycloalkyl, or phenyl, each optionally substituted by 1, 2, or 3occurrences of R⁶) or —O-(3-10 membered heterocyclyl, C₃₋₁₀ cycloalkyl,or phenyl, each optionally substituted by 1, 2, or 3 occurrences of R⁶).In certain embodiments, A² is —N(R⁴)(3-10 membered heterocycloalkyl orC₃₋₁₀ cycloalkyl, each optionally substituted by 1, 2, or 3 occurrencesof R⁶) or —O-(3-10 membered heterocycloalkyl or C₃₋₁₀ cycloalkyl, eachoptionally substituted by 1, 2, or 3 occurrences of R⁶). In certainembodiments, A² is —N(R⁴)(tetrahydropyranyl, morpholinyl, orpiperidinyl, each optionally substituted by 1, 2, or 3 occurrences ofR⁶), —N(R⁴)(C₄₋₆ cycloalkyl optionally substituted by 1, 2, or 3occurrences of R⁶), —O-(tetrahydropyranyl, morpholinyl, or piperidinyl,each optionally substituted by 1, 2, or 3 occurrences of R⁶), or—O—(C₄₋₆ cycloalkyl optionally substituted by 1, 2, or 3 occurrences ofR⁶).

In certain embodiments, A² is located at the 5-position of thepyrazolo[1,5-a]pyrimidinyl. In certain embodiments, n is 1. In certainembodiments, A² is located at the 5-position of thepyrazolo[1,5-a]pyrimidinyl, n is 1, and the R¹ group is located at the7-position of the pyrazolo[1,5-a]pyrimidinyl.

In certain embodiments, A² is located at the 7-position of thepyrazolo[1,5-a]pyrimidinyl. In certain embodiments, n is 1. In certainembodiments, A² is located at the 7-position of thepyrazolo[1,5-a]pyrimidinyl, n is 1, and R¹ group is located at the5-position of the pyrazolo[1,5-a]pyrimidinyl.

In certain embodiments, R¹ represents independently for each occurrenceC₁₋₄ alkyl, C₁₋₄ haloalkyl, —(C₁₋₄ alkylene)-(2-6 membered heteroalkyl),cyclopropyl, halogen, or —N(R⁴)₂. In certain embodiments, R¹ representsindependently for each occurrence C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments,R¹ is methyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R¹ andR² each represent independently for each occurrence hydrogen or C₁₋₄alkyl.

In certain embodiments, R³ and R⁴ each represent independently for eachoccurrence hydrogen, methyl, or ethyl.

In certain embodiments, A¹ is (i) 3-5 membered saturated carbocyclyl, or(ii) a 6-14 membered saturated spirocyclic carbocyclyl, each optionallysubstituted with 1 or 2 C₁₋₄ alkyl groups. In certain embodiments, A¹ isa 3-14 membered saturated carbocyclyl substituted by 0, 1, or 2occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y². In certainembodiments, A¹ is C₃₋₇ cycloalkyl substituted once by Y¹ and 0-1occurrences of Y². In certain embodiments, A¹ is a 5-14 memberedpartially unsaturated carbocyclyl substituted by 0, 1, or 2 occurrencesof Y¹ and 0, 1, 2, or 3 occurrences of Y². In certain embodiments, A¹ isa 8-12 membered bicyclic carbocyclyl that is partially unsaturated or a8-12 membered bicyclic heterocyclyl, each of which is substituted by 0or 1 occurrence of Y¹ and 0, 1, or 2 occurrences of Y². In certainembodiments, A¹ is phenyl substituted once by Y¹ and 0-1 occurrences ofY².

In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted onceby Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is pyridinylsubstituted once by Y¹ and 0-1 occurrences of Y².

In certain embodiments, A¹ is C₃₋₇ cycloalkyl substituted by C₁₋₆alkoxyl. In certain embodiments, A¹ is cyclohexyl substituted by C₁₋₆alkoxyl. In certain embodiments, A¹ is C₃₋₇ cycloalkyl that is notsubstituted. In certain embodiments, A¹ is C₇₋₁₀ cycloalkyl that isspirocyclic and not substituted. In certain embodiments, A¹ iscyclopropyl.

In certain embodiments, A¹ is phenyl substituted by C₂ alkynyl.

In certain embodiments, A¹ is an 8-12 membered bicyclic carbocyclyl thatis partially unsaturated or an 8-12 membered bicyclic heterocyclyl, eachof which is substituted by 0 or 1 occurrence of Y² selected from thegroup consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl, and C₁₋₆ alkoxyl. In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y represents independently for eachoccurrence C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl,hydroxyl, or C₁₋₆ alkoxyl.

In certain embodiments, any occurrence of Y² is independently C₁₋₆alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, or hydroxyl. In certainembodiments, any occurrence of Y² is independently C₁₋₃ alkyl. Incertain embodiments, Y² is C₁₋₆ haloalkyl-substituted C₃₋₆ cycloalkyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a6-10 membered aryl or a 3-10 membered heterocyclyl. In certainembodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 memberedheteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl,furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 memberedheteroalkyl.

In certain embodiments, Y¹ is —O—(C₁₋₇ alkyl). In certain embodiments,Y¹ is —O— butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ is—(C₁₋₃ alkylene)-O-(5-6 membered heteroaryl). In certain embodiments, Y¹is —CH₂—O-(5-6 membered heteroaryl). In certain embodiments, Y¹ is—CH₂—O-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl,thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl,thiazolinyl, or triazolinyl, each of which is substituted by one or twosubstituents independently selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,hydroxyl, C₁₋₆ alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10membered aryl, C₃₋₇ cycloalkyl, —O-(3-6 membered heterocyclyl), —O-(6-10membered aryl), or —O—(C₂₋₆ alkynyl). In certain embodiments, Y¹ is a3-10 membered heterocyclyl selected from the group consisting of a 5-6membered heteroaryl and a 5-6 membered heterocycloalkyl. In certainembodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ isa 5-membered heteroaryl substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₇cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H. In certain embodiments, Y¹ isa 5-membered heteroaryl substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ haloalkyl, hydroxyl, and C₁₋₆ alkoxyl.

In certain embodiments, Y¹ is furanyl, pyrrolyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, or thiazolyl. In certain embodiments, Y¹ isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, orthiazolyl, each of which is substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl. Incertain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, eachof which is substituted by one or two substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆ alkoxyl,cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is C₂₋₆ alkynyl, —C≡C—(C₁₋₆ alkylene)-OR⁴,—C≡C—(C₁₋₆ alkylene)-N(R³)₂, —(C₂₋₄ alkynylene)-(5-6 memberedheteroaryl), or C₂₋₆ alkenyl. In certain embodiments, Y¹ is C₂₋₆alkynyl. In certain embodiments, Y¹ is —C≡CH. In certain embodiments, Y¹is —C≡C—(C₁₋₆ alkylene)-OR⁴. In certain embodiments, Y¹ is —C≡C—(C₁₋₆alkylene)-O—(C₁₋₂ alkyl). In certain embodiments, Y¹ is —C≡C—CH₂—O—CH₃.

In certain embodiments, Y¹ is —O—(C₁₋₇ alkyl). In certain embodiments,Y¹ is —O— butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ isC₂₋₆ alkynyl, —C≡C—(C₁₋₆ alkylene)-OR⁴, —C≡C—(C₁₋₆ alkylene)-N(R³)₂,—(C₂₋₄ alkynylene)-(5-6 membered heteroaryl), or C₂₋₆ alkenyl. Incertain embodiments, Y¹ is —C≡CH. In certain embodiments, Y¹ is—C≡C—(C₁₋₆ alkylene)-OR⁴. In certain embodiments, Y¹ is —C≡C—CH₂—O—CH₃.In certain embodiments, Y¹ is C₂₋₆ alkynyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is —(C₁₋₃ alkylene)-O-(5-6 membered heteroaryl).In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10membered aryl, C₃₋₇ cycloalkyl, —O-(3-6 membered heterocyclyl), —O-(6-10membered aryl), or —O—(C₂₋₆ alkynyl). In certain embodiments, Y¹ is a3-10 membered heterocyclyl selected from the group consisting of a 5-6membered heteroaryl and a 5-6 membered heterocycloalkyl. In certainembodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, orthiazolyl.

The description above describes multiple embodiments relating tocompounds of Formula I. The patent application specifically contemplatesall combinations of the embodiments. For example, the inventioncontemplates a compound of Formula I wherein X¹ is —C(O)N(H)C(H)(CF₃)-ψ,R¹ and R² each represent independently for each occurrence hydrogen orC₁₋₄ alkyl, and A² is phenyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen, hydroxyl, and—N(R⁴)₂.

In certain embodiments, the compound is a compound of Formula I-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ and R² each represent independently for each occurrence        hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄        cyanoalkyl, C₁₋₄ alkoxyl, C₁₋₄ haloalkoxyl, cyclopropyl, cyano,        halogen, hydroxyl, —N(R⁴)₂, —O—(C₁₋₄ alkylene)-C₁₋₆ alkoxyl, or        —(C₁₋₄ alkylene)-(2-6 membered heteroalkyl optionally        substituted by one or more halogen);    -   R³ represents independently for each occurrence hydrogen, C₁₋₆        alkyl, or C₃₋₆ cycloalkyl;    -   R⁴ represents independently for each occurrence hydrogen, C₁₋₄        alkyl, cyclopropyl, or —C(O)R³;    -   R⁵ represents independently for each occurrence C₁₋₄ alkyl or        C₃₋₆ cycloalkyl;    -   R⁶ represents independently for each occurrence C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxyl, cyano, halogen, hydroxyl, or —N(R⁴)₂;    -   R⁷ represents independently for each occurrence halogen,        hydroxyl, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₁₋₄        haloalkoxyl, C₃₋₆ cycloalkyl, —O—(C₃₋₆ cycloalkyl), —O—(C₁₋₆        alkylene)-C₁₋₆ alkoxyl, —(C₁₋₆ alkylene)-CN, —N(R⁴)₂,        —C(O)N(R⁴)₂, or heteroaryl;    -   X¹ is a carbonyl-containing linker selected from —C(O)N(H)(C₁₋₆        haloalkylene)-ψ, —C(O)N(H)(C₁₋₆ alkylene optionally substituted        with C₁₋₄ alkoxyl or C₃₋₆ cycloalkyl)-ψ, —C(O)N(H)(C₃₋₆        cycloalkylene)-ψ, —C(O)N(H)(3-6 membered heterocycloalkylene)-ψ,        —C(O)-(3-6 membered heterocycloalkylene containing at least one        ring —N(H)— group)-ψ, and —C(O)N(H)-ψ, where ψ is a bond to A¹;    -   A¹ is one of the following:        -   a cyclic group selected from a 3-14 membered saturated            carbocyclyl, a 5-14 membered partially unsaturated            carbocyclyl, a 3-16 membered heterocyclyl, or phenyl; each            of which is substituted by 0, 1, or 2 occurrences of Y¹ and            0, 1, 2, or 3 occurrences of Y²; or        -   C₁₋₈ alkyl or C₂₋₆ alkynyl;    -   A² is one of the following:        -   phenyl substituted by 1, 2, or 3 occurrences of R⁷;        -   a cyclic group selected from a 3-12 membered heterocyclyl,            4-12 membered oxoheterocyclyl, or 4-10 membered cycloalkyl;            each of which is optionally substituted by 1, 2, or 3            occurrences of R⁷; or        -   —N(R⁴)(3-10 membered heterocyclyl, C₃₋₁₀ cycloalkyl, or            phenyl, each optionally substituted by 1, 2, or 3            occurrences of R⁶) or —O-(3-10 membered heterocyclyl, C₃₋₁₀            cycloalkyl, or phenyl, each optionally substituted by 1, 2,            or 3 occurrences of R⁶);    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6-10            membered aryl, a 3-10 membered heterocyclyl, or C₃₋₆            halocycloalkyl;        -   3-10 membered heterocyclyl, 6-10 membered aryl, C₃₋₇            cycloalkyl, —O—C₃₋₆ cycloalkyl, —O-(3-6 membered            heterocyclyl), —O-(6-10 membered aryl), or —O—(C₂₋₆            alkynyl); or        -   C₂₋₆ alkynyl, —C≡C—(C₁₋₆ alkylene)-OR⁴, —C≡C—(C₁₋₆            alkylene)-N(R³)₂, —(C₂₋₄ alkynylene)-(5-6 membered            heteroaryl), or C₂₋₆ alkenyl;    -   Y² represents, independently for each occurrence, C₁₋₆ alkyl,        C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,        hydroxyl, C₁₋₆ alkoxyl, —O—(C₁₋₈ haloalkyl), cyano, azido,        —N(R³)₂, —(C₁₋₆ alkylene)-(5-6 membered heterocyclyl), —(C₁₋₆        alkylene)-CO₂R³, —CO₂R³, —C(O)R⁵, —S(O)₂R⁵, —C(O)N(R⁵)₂,        —C(O)N(R³)₂, or C₁₋₆ haloalkyl-substituted C₃₋₆ cycloalkyl; and    -   n is 1, 2, or 3;    -   provided that when A² is a 5-6 membered heterocycloalkyl and X¹        is —C(O)N(H)-ψ, then A¹ is not -phenyl-(C₁₋₆ alkyl).

Definitions of the variables in Formula I-1 above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where X¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-ψ, R¹ and R² eachrepresent independently for each occurrence hydrogen or C₁₋₄ alkyl, andA² is phenyl substituted by 1 or 2 R⁷.

Accordingly, in certain embodiments, X¹ is —C(O)N(H)(C₁₋₆haloalkylene)-ψ. In certain embodiments, X¹ is —C(O)N(H)C(H)(CF₃)-ψ. Incertain embodiments, X¹ is —C(O)N(H)(C₁₋₆ alkylene)-ψ. In certainembodiments, X¹ is —C(O)N(H)(C(CH₃)₂)-ψ or —C(O)N(H)(C(H)(CH₃))-ψ. Incertain embodiments, X¹ is —C(O)N(H)(C₁₋₆ alkylene substituted with C₁₋₄alkoxyl)-ψ. In certain embodiments, X¹ is —C(O)N(H)(C₁₋₆ alkylenesubstituted with C₃₋₆ cycloalkyl)-ψ. In certain embodiments, X¹ is—C(O)N(H)(C₃₋₆ cycloalkylene)-ψ. In certain embodiments, X¹ is—C(O)N(H)(3-6 membered heterocycloalkylene)-ψ. In certain embodiments,X¹ is —C(O)N(H)-ψ.

In certain embodiments, A² is phenyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,hydroxyl, and —N(R⁴)₂. In certain embodiments, A² is phenyl substitutedby 1, 2, or 3 substituents independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl,cyano, and halogen, wherein there is at least one substituent at ameta-position on the phenyl group. In certain embodiments, A² is phenylsubstituted at one meta-position by C₁₋₄ alkoxyl, cyano, or halogen, andoptionally substituted elsewhere on the phenyl group by C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, or halogen. In certainembodiments, A² is phenyl substituted by C₁₋₄ alkoxyl, cyano, orhalogen. In certain embodiments, A² is phenyl substituted at onemeta-position by C₁₋₄ alkoxyl, cyano, or halogen.

In certain embodiments, A² is a 5-12 membered heterocyclyl optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂. In certainembodiments, A² is a 5-6 membered heteroaryl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano,halogen, hydroxyl, and —N(R⁴)₂. In certain embodiments, A² is a 5-6membered heteroaryl selected from the group consisting of pyridinyl,pyrimidinyl, pyrazinyl, furanyl, pyrrolyl, thiophenyl, oxazolyl,isoxazolyl, and thiazolyl, each of which is optionally substituted by 1,2, or 3 substituents independently selected from the group consisting ofC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano,halogen, hydroxyl, and —N(R⁴)₂. In certain embodiments, A² is pyridinyloptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl,C₃₋₅ cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂. In certainembodiments, A² is 3-pyridinyl optionally substituted by 1 or 2substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, andhalogen.

In certain embodiments, A² is a 5-6 membered heterocycloalkyl optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂. In certainembodiments, A² is a 5-6 membered heterocycloalkyl selected from thegroup consisting of morpholinyl, piperidinyl, pyrrolidinyl,tetrahydropyranyl, and tetrahydrofuranyl, each of which is optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂.

In certain embodiments, A² is a 5-10 membered cycloalkyl optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, hydroxyl, and —N(R⁴)₂. In certainembodiments, A² is a 5-6 membered cycloalkyl optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano,halogen, hydroxyl, and —N(R⁴)₂.

In certain embodiments, A² is —N(R⁴)(3-10 membered heterocyclyl, C₃₋₁₀cycloalkyl, or phenyl, each optionally substituted by 1, 2, or 3occurrences of R⁶) or —O-(3-10 membered heterocyclyl, C₃₋₁₀ cycloalkyl,or phenyl, each optionally substituted by 1, 2, or 3 occurrences of R⁶).In certain embodiments, A² is —N(R⁴)(3-10 membered heterocycloalkyl orC₃₋₁₀ cycloalkyl, each optionally substituted by 1, 2, or 3 occurrencesof R⁶) or —O-(3-10 membered heterocycloalkyl or C₃₋₁₀ cycloalkyl, eachoptionally substituted by 1, 2, or 3 occurrences of R⁶). In certainembodiments, A² is —N(R⁴)(tetrahydropyranyl, morpholinyl, orpiperidinyl, each optionally substituted by 1, 2, or 3 occurrences ofR⁶), —N(R⁴)(C₄₋₆ cycloalkyl optionally substituted by 1, 2, or 3occurrences of R⁶), —O-(tetrahydropyranyl, morpholinyl, or piperidinyl,each optionally substituted by 1, 2, or 3 occurrences of R⁶), or—O—(C₄₋₆ cycloalkyl optionally substituted by 1, 2, or 3 occurrences ofR⁶).

In certain embodiments, A² is located at the 5-position of thepyrazolo[1,5-a]pyrimidinyl. In certain embodiments, n is 1. In certainembodiments, A² is located at the 5-position of thepyrazolo[1,5-a]pyrimidinyl, n is 1, and the R¹ group is located at the7-position of the pyrazolo[1,5-a]pyrimidinyl.

In certain embodiments, A² is located at the 7-position of thepyrazolo[1,5-a]pyrimidinyl. In certain embodiments, n is 1. In certainembodiments, A² is located at the 7-position of thepyrazolo[1,5-a]pyrimidinyl, n is 1, and R¹ group is located at the5-position of the pyrazolo[1,5-a]pyrimidinyl.

In certain embodiments, R¹ represents independently for each occurrenceC₁₋₄ alkyl, C₁₋₄ haloalkyl, —(C₁₋₄ alkylene)-(2-6 membered heteroalkyl),cyclopropyl, halogen, or —N(R⁴)₂. In certain embodiments, R¹ representsindependently for each occurrence C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments,R¹ is methyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R¹ andR² each represent independently for each occurrence hydrogen or C₁₋₄alkyl.

In certain embodiments, R³ and R⁴ each represent independently for eachoccurrence hydrogen, methyl, or ethyl.

In certain embodiments, A¹ is a 3-14 membered saturated carbocyclylsubstituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3occurrences of Y². In certain embodiments, A¹ is C₃₋₇ cycloalkylsubstituted once by Y¹ and 0-1 occurrences of Y². In certainembodiments, A¹ is a 5-14 membered partially unsaturated carbocyclylsubstituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3occurrences of Y². In certain embodiments, A¹ is a 8-12 memberedbicyclic carbocyclyl that is partially unsaturated or a 8-12 memberedbicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrenceof Y¹ and 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ isphenyl substituted once by Y¹ and 0-1 occurrences of Y².

In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted onceby Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is pyridinylsubstituted once by Y¹ and 0-1 occurrences of Y².

In certain embodiments, A¹ is C₃₋₇ cycloalkyl substituted by C₁₋₆alkoxyl. In certain embodiments, A¹ is cyclohexyl substituted by C₁₋₆alkoxyl. In certain embodiments, A¹ is C₃₋₇ cycloalkyl that is notsubstituted. In certain embodiments, A¹ is C₇₋₁₀ cycloalkyl that isspirocyclic and not substituted. In certain embodiments, A¹ iscyclopropyl.

In certain embodiments, A¹ is phenyl substituted by C₂ alkynyl.

In certain embodiments, A¹ is an 8-12 membered bicyclic carbocyclyl thatis partially unsaturated or an 8-12 membered bicyclic heterocyclyl, eachof which is substituted by 0 or 1 occurrence of Y² selected from thegroup consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl, and C₁₋₆ alkoxyl. In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y² represents independently for eachoccurrence C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl,hydroxyl, or C₁₋₆ alkoxyl.

In certain embodiments, any occurrence of Y² is independently C₁₋₆alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, or hydroxyl. In certainembodiments, any occurrence of Y² is independently C₁₋₃ alkyl. Incertain embodiments, Y² is C₁₋₆ haloalkyl-substituted C₃₋₆ cycloalkyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a6-10 membered aryl or a 3-10 membered heterocyclyl. In certainembodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 memberedheteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl,furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 memberedheteroalkyl.

In certain embodiments, Y¹ is —O—(C₁₋₇ alkyl). In certain embodiments,Y¹ is —O— butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ is—(C₁₋₃ alkylene)-O-(5-6 membered heteroaryl). In certain embodiments, Y¹is —CH₂—O-(5-6 membered heteroaryl). In certain embodiments, Y¹ is—CH₂—O-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl,thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl,thiazolinyl, or triazolinyl, each of which is substituted by one or twosubstituents independently selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,hydroxyl, C₁₋₆ alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10membered aryl, C₃₋₇ cycloalkyl, —O-(3-6 membered heterocyclyl), —O-(6-10membered aryl), or —O—(C₂₋₆ alkynyl). In certain embodiments, Y¹ is a3-10 membered heterocyclyl selected from the group consisting of a 5-6membered heteroaryl and a 5-6 membered heterocycloalkyl. In certainembodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ isa 5-membered heteroaryl substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₇cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H. In certain embodiments, Y¹ isa 5-membered heteroaryl substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ haloalkyl, hydroxyl, and C₁₋₆ alkoxyl.

In certain embodiments, Y¹ is furanyl, pyrrolyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, or thiazolyl. In certain embodiments, Y¹ isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, orthiazolyl, each of which is substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl. Incertain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, eachof which is substituted by one or two substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆ alkoxyl,cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is C₂₋₆ alkynyl, —C≡C—(C₁₋₆ alkylene)-OR⁴,—C≡C—(C₁₋₆ alkylene)-N(R³)₂, —(C₂₋₄ alkynylene)-(5-6 memberedheteroaryl), or C₂₋₆ alkenyl. In certain embodiments, Y¹ is C₂₋₆alkynyl. In certain embodiments, Y¹ is —C≡CH. In certain embodiments, Y¹is —C≡C—(C₁₋₆ alkylene)-OR⁴. In certain embodiments, Y¹ is —C≡C—(C₁₋₆alkylene)-O—(C₁₋₂ alkyl). In certain embodiments, Y¹ is —C≡C—CH₂—O—CH₃.

In certain embodiments, Y¹ is —O—(C₁₋₇ alkyl). In certain embodiments,Y¹ is —O— butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ isC₂₋₆ alkynyl, —C≡C—(C₁₋₆ alkylene)-OR⁴, —C≡C—(C₁₋₆ alkylene)-N(R³)₂,—(C₂₋₄ alkynylene)-(5-6 membered heteroaryl), or C₂₋₆ alkenyl. Incertain embodiments, Y¹ is —C≡CH. In certain embodiments, Y¹ is—C≡C—(C₁₋₆ alkylene)-OR⁴. In certain embodiments, Y¹ is —C≡C—CH₂—O—CH₃.In certain embodiments, Y¹ is C₂₋₆ alkynyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is —(C₁₋₃ alkylene)-O-(5-6 membered heteroaryl).In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10membered aryl, C₃₋₇ cycloalkyl, —O-(3-6 membered heterocyclyl), —O-(6-10membered aryl), or —O—(C₂₋₆ alkynyl). In certain embodiments, Y¹ is a3-10 membered heterocyclyl selected from the group consisting of a 5-6membered heteroaryl and a 5-6 membered heterocycloalkyl. In certainembodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, orthiazolyl.

The description above describes multiple embodiments relating tocompounds of Formula I-1. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula I-1 wherein X¹ is—C(O)N(H)C(H)(CF₃)-ψ, R¹ and R² each represent independently for eachoccurrence hydrogen or C₁₋₄ alkyl, and A² is phenyl substituted by 1, 2,or 3 substituents independently selected from the group consisting ofC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano,halogen, hydroxyl, and —N(R⁴)₂.

In certain embodiments, the compound is a compound of Formula I-A:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ is C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, —(C₁₋₄        alkylene)-(C₁₋₄ alkoxyl), cyclopropyl, chloro, or fluoro;    -   R² is hydrogen;    -   R³ and R⁴ each represent independently for each occurrence        hydrogen or C₁₋₄ alkyl;    -   X¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-ψ or —C(O)N(H)(C₁₋₆        alkylene)-ψ, where ψ is a bond to A¹;    -   A¹ is a cyclic group selected from:        -   C₃₋₁₀ cycloalkyl substituted by 0 or 1 occurrence of Y¹ and            0, 1, or 2 occurrences of Y²; and        -   phenyl substituted by 0 or 1 occurrence of Y¹ and 0, 1, or 2            occurrences of Y²;    -   A² is a cyclic group selected from:        -   phenyl substituted by 1, 2, or 3 substituents independently            selected from the group consisting of C₁₋₄ alkyl, C₁₋₄            haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,            and hydroxyl; and        -   a 5-12 membered heterocyclyl optionally substituted by 1, 2,            or 3 substituents independently selected from the group            consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅            cycloalkyl, cyano, halogen, and hydroxyl;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl or —O—(C₂₋₆ alkynyl); or        -   C₂₋₆ alkynyl or —C≡C—(C₁₋₆ alkylene)-OR⁴; and    -   Y² represents, independently for each occurrence, C₁₋₆ alkyl,        C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,        hydroxyl, C₁₋₆ alkoxyl, cyano, or —N(R³)₂; provided that when        X¹-A¹ is —C(O)N(H)(C₁₋₆ alkylene)-(unsubstituted C₅₋₈        cycloalkyl), A² is not a 5 membered heteroaryl optionally        substituted by 1, 2, or 3 substituents independently selected        from the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄        alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen, and hydroxyl.

Definitions of the variables in Formula I-A above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where —C(O)N(H)(C₁₋₆ haloalkylene)-ψy, R¹ is C₁₋₄ alkyl or C₁₋₄haloalkyl, and A² is phenyl substituted by 1 or 2 substituentsindependently selected from the group consisting of C₁₋₄ haloalkyl, C₁₋₄alkoxyl, C₃₋₅ cycloalkyl, cyano, and halogen.

Accordingly, in certain embodiments, R¹ represents independently foreach occurrence methyl, halomethyl, —(CH₂)₁₋₂—O—(C₁₋₃ alkyl),cyclopropyl, chloro, or fluoro. In certain embodiments, R¹ is C₁₋₄ alkylor C₁₋₄ haloalkyl. In certain embodiments, R¹ is methyl.

In certain embodiments, A¹ is C₃₋₇ cycloalkyl substituted once by Y¹ and0-1 occurrences of Y². In certain embodiments, A¹ is cyclohexylsubstituted once by Y¹. In certain embodiments, A¹ is C₃₋₇ cycloalkylthat is not substituted. In certain embodiments, A¹ is C₇₋₁₀ cycloalkylthat is spirocyclic and not substituted. In certain embodiments, A¹ iscyclopropyl.

In certain embodiments, A¹ is cyclohexyl or a 8-membered bicycliccycloalkyl, each of which is substituted once by Y and 0-1 occurrencesof Y².

In certain embodiments, A¹ is phenyl substituted by 0 or 1 occurrence ofY¹ and 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ isphenyl substituted by 1 occurrence of Y¹.

In certain embodiments, Y² is independently C₁₋₃ alkyl, halogen, or C₁₋₃haloalkyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl. In certainembodiments, Y¹ is —O—(C₁₋₇ alkyl). In certain embodiments, Y¹ is—O-butyl, —O-pentyl, or —O-hexyl.

In certain embodiments, A² is phenyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, and halogen. In certainembodiments, A² is phenyl substituted by 1, 2, or 3 substituentsindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, and halogen, whereinthere is at least one substituent at a meta-position on the phenylgroup. In certain embodiments, A² is phenyl substituted at onemeta-position by C₁₋₄ alkoxyl, cyano, or halogen, and optionallysubstituted elsewhere on the phenyl group by C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, or halogen. In certain embodiments, A² isphenyl substituted by C₁₋₄ alkoxyl, cyano, or halogen. In certainembodiments, A² is phenyl substituted at one meta-position by C₁₋₄alkoxyl, cyano, or halogen.

In certain embodiments, A² is a 5-12 membered heterocyclyl optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, and hydroxyl. In certain embodiments, A² isa 5-6 membered heteroaryl optionally substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,and hydroxyl. In certain embodiments, A² is a 5-6 membered heteroarylselected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl,furanyl, pyrrolyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl,isothiazolyl, and thiazolyl, each of which is optionally substituted by1, 2, or 3 substituents independently selected from the group consistingof C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano,halogen, and hydroxyl. In certain embodiments, A² is a 5-6 memberedheteroaryl selected from the group consisting of pyridinyl, pyrimidinyl,pyrazinyl, furanyl, pyrrolyl, thiophenyl, oxazolyl, isoxazolyl, andthiazolyl, each of which is optionally substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,and hydroxyl. In certain embodiments, A² is pyridinyl optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, and hydroxyl. In certain embodiments, A² is3-pyridinyl optionally substituted by 1 or 2 3 substituentsindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, and halogen.

In certain embodiments, A² is a 5-6 membered heterocycloalkyl optionallysubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅cycloalkyl, cyano, halogen, and hydroxyl. In certain embodiments, A² isa 5-6 membered heterocycloalkyl selected from the group consisting ofmorpholinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, andtetrahydrofuranyl, each of which is optionally substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,and hydroxyl.

In certain embodiments, X¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-ψ. In certainembodiments, X¹ is —C(O)N(H)C(H)(CF₃)-ψ. In certain embodiments, X¹ is—C(O)N(H)(C₁₋₆ alkylene)-ψ. In certain embodiments, X¹ is—C(O)N(H)(C(CH₃)₂)-ψ or —C(O)N(H)(C—(H)(CH₃))-ψ.

The description above describes multiple embodiments relating tocompounds of Formula I-A. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula I-A wherein X¹ is—C(O)N(H)C(H)(CF₃)-ψ, R¹ is C₁₋₄ alkyl or C₁₋₄ haloalkyl, and A² isphenyl substituted at one meta-position by C₁₋₄ alkoxyl, cyano, orhalogen, and optionally substituted elsewhere on the phenyl group byC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, or halogen.

In certain embodiments, the substituted pyrazolo[1,5-a]pyrimidinylcarboxamide or related organic compound is a compound embraced byFormula II:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ and R² each represent independently for each occurrence        hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄        cyanoalkyl, C₁₋₄ alkoxyl, C₁₋₄ haloalkoxyl, cyclopropyl, cyano,        halogen, hydroxyl, —N(R⁴)₂, —O—(C₁₋₄ alkylene)-C₁₋₆ alkoxyl, or        —(C₁₋₄ alkylene)-(2-6 membered heteroalkyl optionally        substituted by one or more halogen);    -   R³ represents independently for each occurrence hydrogen, C₁₋₆        alkyl, or C₃₋₆ cycloalkyl;    -   R⁴ represents independently for each occurrence hydrogen, C₁₋₄        alkyl, cyclopropyl, or —C(O)R³;    -   R⁵ represents independently for each occurrence C₁₋₄ alkyl or        C₃₋₆ cycloalkyl;    -   X¹ is a carbonyl-containing linker selected from —C(O)N(H)(C₁₋₆        haloalkylene)-ψ, —C(O)N(H)(C₁₋₆ alkylene substituted with C₁₋₄        alkoxyl or C₃₋₆ cycloalkyl)-ψ, —C(O)N(H)(C₃₋₆ cycloalkylene)-ψ,        —C(O)N(H)(3-6 membered heterocycloalkylene)-ψ, —C(O)N(H)C(O)-ψ,        and —C(O)N(H)C(O)(C₁₋₆ alkylene)-ψ; where ψ is a bond to A¹;    -   A¹ is one of the following:        -   a cyclic group selected from a 3-14 membered saturated            carbocyclyl, a 5-14 membered partially unsaturated            carbocyclyl, a 3-16 membered heterocyclyl, or phenyl; each            of which is substituted by 0, 1, or 2 occurrences of Y¹ and            0, 1, 2, or 3 occurrences of Y²; or        -   C₁₋₈ alkyl or C₂₋₆ alkynyl;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl optionally substituted by a 6-10            membered aryl, a 3-10 membered heterocyclyl, or C₃₋₆            halocycloalkyl;        -   3-10 membered heterocyclyl, 6-10 membered aryl, C₃₋₇            cycloalkyl, —O—C₃₋₆ cycloalkyl, —O-(3-6 membered            heterocyclyl), —O-(6-10 membered aryl), or —O—(C₂₋₆            alkynyl); or        -   C₂₋₆ alkynyl, —C≡C—(C₁₋₆ alkylene)-OR⁴, —C≡C—(C₁₋₆            alkylene)-N(R³)₂, —(C₂₋₄ alkynylene)-(5-6 membered            heteroaryl), or C₂₋₆ alkenyl;    -   Y² represents, independently for each occurrence, C₁₋₆ alkyl,        C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,        hydroxyl, C₁₋₆ alkoxyl, —O—(C₁₋₈ haloalkyl), cyano, azido,        —N(R³)₂, —(C₁₋₆ alkylene)-(5-6 membered heterocyclyl), —(C₁₋₆        alkylene)-CO₂R³, —CO₂R³, —C(O)R⁵, —S(O)₂R⁵, —C(O)N(R⁵)₂,        —C(O)N(R³)₂, or C₁₋₆ haloalkyl-substituted C₃₋₆ cycloalkyl;    -   m is 1 or 2; and    -   n is 1, 2, or 3;    -   provided that when X¹ is —C(O)N(H)(C₃₋₆ cycloalkylene)-ψ or        —C(O)N(H)(3-6 membered heterocycloalkylene)-ψ, then A¹ is not a        5-membered heterocyclyl, C₁₋₈ alkyl, or C₂ alkynyl.

Definitions of the variables in Formula II above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where X¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-ψ, R¹ and R² eachrepresent independently for each occurrence hydrogen or C₁₋₄ alkyl, andA¹ is a 3-14 membered saturated carbocyclyl.

Accordingly, in certain embodiments, X¹ is —C(O)N(H)(C₁₋₆haloalkylene)-ψ. In certain embodiments, X¹ is —C(O)N(H)C(H)(CF₃)-ψ. Incertain embodiments, X¹ is —C(O)N(H)(C₁₋₆ alkylene substituted with C₁₋₄alkoxyl)-ψ. In certain embodiments, X¹ is —C(O)N(H)C(H)(CH₂OCH₃)-ψ. Incertain embodiments, X¹ is —C(O)N(H)(C₁₋₆ alkylene substituted with C₃₋₆cycloalkyl)-ψ. In certain embodiments, X¹ is —C(O)N(H)(C₃₋₆cycloalkylene)-ψ.

In certain embodiments, n is 2. In certain embodiments, R¹ groups arelocated at the 5 and 7 positions of the pyrazolo[1,5-a]pyrimidinyl.

In certain embodiments, R¹ represents independently for each occurrenceC₁₋₄ alkyl, C₁₋₄ haloalkyl, —(C₁₋₄ alkylene)-(2-6 membered heteroalkyl),cyclopropyl, halogen, or —N(R⁴)₂. In certain embodiments, R¹ representsindependently for each occurrence C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments,R¹ is methyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R¹ andR² each represent independently for each occurrence hydrogen or C₁₋₄alkyl.

In certain embodiments, R³ and R⁴ each represent independently for eachoccurrence hydrogen, methyl, or ethyl.

In certain embodiments, A¹ is a 3-14 membered saturated carbocyclylsubstituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3occurrences of Y². In certain embodiments, A¹ is a 3-14 memberedsaturated carbocyclyl. In certain embodiments, A¹ is C₃₋₇ cycloalkylsubstituted once by Y¹ and 0-1 occurrences of Y². In certainembodiments, A¹ is a 5-14 membered partially unsaturated carbocyclylsubstituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3occurrences of Y². In certain embodiments, A¹ is a 8-12 memberedbicyclic carbocyclyl that is partially unsaturated or a 8-12 memberedbicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrenceof Y¹ and 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ isphenyl substituted once by Y¹ and 0-1 occurrences of Y².

In certain embodiments, A¹ is a 5-6 membered heteroaryl substituted onceby Y¹ and 0-1 occurrences of Y². In certain embodiments, A¹ is pyridinylsubstituted once by Y¹ and 0-1 occurrences of Y².

In certain embodiments, A¹ is C₃₋₇ cycloalkyl substituted by C₁₋₆alkoxyl. In certain embodiments, A¹ is cyclohexyl substituted by C₁₋₆alkoxyl. In certain embodiments, A¹ is C₃₋₇ cycloalkyl that is notsubstituted. In certain embodiments, A¹ is C₇₋₁₀ cycloalkyl that isspirocyclic and not substituted. In certain embodiments, A¹ iscyclopropyl.

In certain embodiments, A¹ is phenyl substituted by C₂ alkynyl.

In certain embodiments, A¹ is an 8-12 membered bicyclic carbocyclyl thatis partially unsaturated or an 8-12 membered bicyclic heterocyclyl, eachof which is substituted by 0 or 1 occurrence of Y² selected from thegroup consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆haloalkyl, hydroxyl, and C₁₋₆ alkoxyl. In certain embodiments, A¹ is

wherein m is 0, 1, or 2; and Y represents independently for eachoccurrence C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl,hydroxyl, or C₁₋₆ alkoxyl.

In certain embodiments, any occurrence of Y² is independently C₁₋₆alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, or hydroxyl. In certainembodiments, any occurrence of Y² is independently C₁₋₃ alkyl. Incertain embodiments, Y² is C₁₋₆ haloalkyl-substituted C₃₋₆ cycloalkyl.

In certain embodiments, Y¹ is —O—(C₁₋₇ alkyl). In certain embodiments,Y¹ is —O— butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ isC₂₋₆ alkynyl, —C≡C—(C₁₋₆ alkylene)-OR⁴, —C≡C—(C₁₋₆ alkylene)-N(R³)₂,—(C₂₋₄ alkynylene)-(5-6 membered heteroaryl), or C₂₋₆ alkenyl. Incertain embodiments, Y¹ is —C≡CH. In certain embodiments, Y¹ is—C≡C—(C₁₋₆ alkylene)-OR⁴. In certain embodiments, Y¹ is —C≡C—CH₂—O—CH₃.In certain embodiments, Y¹ is C₂₋₆ alkynyl.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a6-10 membered aryl or a 3-10 membered heterocyclyl. In certainembodiments, Y¹ is a 2-8 membered heteroalkyl substituted by a 3-10membered heterocyclyl. In certain embodiments, Y¹ is a 2-8 memberedheteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl,furanyl, or pyridinyl. In certain embodiments, Y¹ is a 2-8 memberedheteroalkyl.

In certain embodiments, Y¹ is —O—(C₁₋₇ alkyl). In certain embodiments,Y¹ is —O— butyl, —O-pentyl, or —O-hexyl. In certain embodiments, Y¹ is—(C₁₋₃ alkylene)-O-(5-6 membered heteroaryl). In certain embodiments, Y¹is —CH₂—O-(5-6 membered heteroaryl). In certain embodiments, Y¹ is—CH₂—O-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl,thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl,oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl,thiazolinyl, or triazolinyl, each of which is substituted by one or twosubstituents independently selected from the group consisting of C₁₋₆alkyl, C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,hydroxyl, C₁₋₆ alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10membered aryl, C₃₋₇ cycloalkyl, —O-(3-6 membered heterocyclyl), —O-(6-10membered aryl), or —O—(C₂₋₆ alkynyl). In certain embodiments, Y¹ is a3-10 membered heterocyclyl selected from the group consisting of a 5-6membered heteroaryl and a 5-6 membered heterocycloalkyl. In certainembodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ isa 5-membered heteroaryl substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₇cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H. In certain embodiments, Y¹ isa 5-membered heteroaryl substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ haloalkyl, hydroxyl, and C₁₋₆ alkoxyl.

In certain embodiments, Y¹ is furanyl, pyrrolyl, thiophenyl, imidazolyl,pyrazolyl, oxazolyl, or thiazolyl. In certain embodiments, Y¹ isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, orthiazolyl, each of which is substituted by one or two substituentsindependently selected from the group consisting of C₁₋₆ alkyl, C₃₋₆cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆alkoxyl, cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl. Incertain embodiments, Y¹ is pyridinyl, pyrimidinyl, pyrazinyl,isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, eachof which is substituted by one or two substituents independentlyselected from the group consisting of C₁₋₆ alkyl, C₃₋₆ cycloalkyl,halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, hydroxyl, C₁₋₆ alkoxyl,cyano, —N(R⁴)₂, amide, and —CO₂H.

In certain embodiments, Y¹ is C₂₋₆ alkynyl, —C≡C—(C₁₋₆ alkylene)-OR⁴,—C≡C—(C₁₋₆ alkylene)-N(R³)₂, —(C₂₋₄ alkynylene)-(5-6 memberedheteroaryl), or C₂₋₆ alkenyl. In certain embodiments, Y¹ is C₂₋₆alkynyl. In certain embodiments, Y¹ is —C≡CH. In certain embodiments, Y¹is —C≡C—(C₁₋₆ alkylene)-OR⁴. In certain embodiments, Y¹ is —C≡C—(C₁₋₆alkylene)-O—(C₁₋₂ alkyl). In certain embodiments, Y¹ is —C≡C—CH₂—O—CH₃.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl optionallysubstituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. Incertain embodiments, Y¹ is —(C₁₋₃ alkylene)-O-(5-6 membered heteroaryl).In certain embodiments, Y¹ is a 3-10 membered heterocyclyl, 6-10membered aryl, C₃₋₇ cycloalkyl, —O-(3-6 membered heterocyclyl), —O-(6-10membered aryl), or —O—(C₂₋₆ alkynyl). In certain embodiments, Y¹ is a3-10 membered heterocyclyl selected from the group consisting of a 5-6membered heteroaryl and a 5-6 membered heterocycloalkyl. In certainembodiments, Y¹ is 5-membered heteroaryl. In certain embodiments, Y¹ isfuranyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, orthiazolyl.

The description above describes multiple embodiments relating tocompounds of Formula II. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula II wherein X¹ is—C(O)N(H)(C₁₋₆ haloalkylene)-ψ, R¹ and R² each represent independentlyfor each occurrence hydrogen or C₁₋₄ alkyl, and A¹ is a 3-14 memberedsaturated carbocyclyl.

In certain embodiments, the substituted pyrazolo[1,5-a]pyrimidinylcarboxamide or related organic compound is a compound embraced byFormula II-A:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ represents independently for each occurrence C₁₋₄ alkyl, C₁₋₄        haloalkyl, C₁₋₄ alkoxyl, —(C₁₋₄ alkylene)-(C₁₋₄ alkoxyl),        cyclopropyl, chloro, or fluoro;    -   R² is hydrogen;    -   R³ and R⁴ each represent independently for each occurrence        hydrogen or C₁₋₄ alkyl;    -   X¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-ψ or —C(O)N(H)(C₁₋₆ alkylene        substituted with C₁₋₄ alkoxyl or C₃₋₆ cycloalkyl)-ψ, where ψ is        a bond to A¹;    -   A¹ is a cyclic group selected from:        -   C₃₋₁₀ cycloalkyl substituted by 0 or 1 occurrence of Y¹ and            0, 1, or 2 occurrences of Y²; and        -   phenyl substituted by 0 or 1 occurrence of Y¹ and 0, 1, or 2            occurrences of Y²;    -   Y¹ represents, independently for each occurrence, one of the        following:        -   2-8 membered heteroalkyl or —O—(C₂₋₆ alkynyl); or        -   C₂₋₆ alkynyl or —C≡C—(C₁₋₆ alkylene)-OR⁴; and    -   Y² represents, independently for each occurrence, C₁₋₆ alkyl,        C₃₋₆ cycloalkyl, halogen, C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl,        hydroxyl, C₁₋₆ alkoxyl, cyano, or —N(R³)₂.

Definitions of the variables in Formula II-A above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where X¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-ψ, R¹ is C₁₋₄ alkyl orC₁₋₄ haloalkyl, and A¹ is a C₃₋₁₀ cycloalkyl substituted by 0 or 1occurrence of Y¹ and 0, 1, or 2 occurrences of Y².

Accordingly, in certain embodiments, R¹ represents independently foreach occurrence methyl, halomethyl, —(CH₂)₁₋₂—O—(C₁₋₃ alkyl),cyclopropyl, chloro, or fluoro. In certain embodiments, R¹ is C₁₋₄ alkylor C₁₋₄ haloalkyl. In certain embodiments, R¹ is methyl.

In certain embodiments, X¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-ψ. In certainembodiments, X¹ is —C(O)N(H)C(H)(CF₃)-ψ.

In certain embodiments, A¹ is a C₃₋₁₀ cycloalkyl substituted by 0 or 1occurrence of Y¹ and 0, 1, or 2 occurrences of Y². In certainembodiments, A¹ is C₃₋₇ cycloalkyl substituted once by Y¹ and 0-1occurrences of Y². In certain embodiments, A¹ is cyclohexyl substitutedonce by Y¹. In certain embodiments, A¹ is C₃₋₇ cycloalkyl that is notsubstituted. In certain embodiments, A¹ is C₇₋₁₀ cycloalkyl that isspirocyclic and not substituted. In certain embodiments, A¹ iscyclopropyl.

In certain embodiments, A¹ is phenyl substituted by 0 or 1 occurrence ofY¹ and 0, 1, or 2 occurrences of Y². In certain embodiments, A¹ isphenyl substituted by 1 occurrence of Y¹.

In certain embodiments, Y¹ is a 2-8 membered heteroalkyl. In certainembodiments, Y¹ is —O—(C₁₋₇ alkyl). In certain embodiments, Y¹ is—O-butyl, —O-pentyl, or —O-hexyl.

The description above describes multiple embodiments relating tocompounds of Formula II-A. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula II-A wherein X¹ is—C(O)N(H)(C₁₋₆ haloalkylene)-ψ, R¹ is C₁₋₄ alkyl or C₁₋₄ haloalkyl, andA¹ is a C₃₋₁₀ cycloalkyl substituted by 0 or 1 occurrence of Y¹ and 0,1, or 2 occurrences of Y².

In certain embodiments, the substituted pyrazolo[1,5-a]pyrimidinylcarboxamide or related organic compound is a compound embraced byFormula III:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ and R² each represent independently for each occurrence        hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, C₁₋₄        cyanoalkyl, C₁₋₄ alkoxyl, C₁₋₄ haloalkoxyl, cyclopropyl, cyano,        halogen, hydroxyl, —N(R⁴)₂, —O—(C₁₋₄ alkylene)-C₁₋₆ alkoxyl, or        —(C₁₋₄ alkylene)-(2-6 membered heteroalkyl optionally        substituted by one or more halogen);    -   R³ represents independently for each occurrence hydrogen, C₁₋₆        alkyl, or C₃₋₆ cycloalkyl;    -   R⁴ represents independently for each occurrence hydrogen, C₁₋₄        alkyl, cyclopropyl, or —C(O)R³;    -   R⁵ is hydrogen or C₁₋₆ alkyl;    -   R⁶ is a bond or C₁₋₆ alkylene;    -   X¹-A¹ is one of the following:        -   —C(O)N(H)(C₁₋₆ haloalkylene)-A¹, —C(O)N(H)(C₁₋₆ alkylene            substituted with C₁₋₄ alkoxyl)-A¹, —C(O)N(H)(C₃₋₆            cycloalkylene)-A¹, —C(O)N(H)(3-6 membered            heterocycloalkylene)-A¹, —C(O)-(3-6 membered            heterocycloalkylene containing at least one ring —N(H)—            group)-A¹, or —C(O)N(H)-A¹, where A¹ is C₃₋₁₀ cycloalkyl            optionally substituted with 1 or 2 C₁₋₄ alkyl groups;        -   —C(O)N(H)C(C₁₋₆ alkyl)₂-R⁶-A¹ or —C(O)N(H)C(C₃₋₆            alkyl)(R⁵)—R⁶-A¹, where A¹ is C₃₋₁₀ cycloalkyl optionally            substituted with 1 or 2 C₁₋₄ alkyl groups;        -   —C(O)N(H)(C₁₋₆ alkylene)-A¹ or —C(O)N(H)(C₁₋₆ alkylene            substituted with C₃₋₆ cycloalkyl)-A¹, where A¹ is a C₆₋₁₀            monocyclic or spirocyclic cycloalkyl optionally substituted            with 1 or 2 C₁₋₄ alkyl groups;        -   —C(O)N(H)C(O)-A¹ or —C(O)N(H)C(O)(C₁₋₆ alkylene)-A¹, where            A¹ is a C₆₋₁₀ monocyclic or spirocyclic cycloalkyl            optionally substituted with 1 or 2 C₁₋₄ alkyl groups;    -   m is 1 or 2; and    -   n is 1, 2, or 3;    -   provided that when X is —C(O)N(H)-ψ and A¹ is a C₅₋₇ cycloalkyl        optionally substituted with 1 or 2 C₁₋₄ alkyl groups; then R¹ is        other than C₁₋₄ alkyl and C₁₋₄ haloalkyl.

Definitions of the variables in Formula III above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where X¹ is —C(O)N(H)(C₁₋₆ alkylene)-ψ, and R¹ and R² eachrepresent independently for each occurrence hydrogen or C₁₋₄ alkyl.

Accordingly, in certain embodiments, R¹ represents independently foreach occurrence C₁₋₄ alkyl, C₁₋₄ haloalkyl, —(C₁₋₄ alkylene)-(2-6membered heteroalkyl), cyclopropyl, halogen, or —N(R⁴)₂. In certainembodiments, R¹ represents independently for each occurrence C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, cyclopropyl, cyano, chloro, or fluoro. Incertain embodiments, R¹ is methyl.

In certain embodiments, n is 2. In certain embodiments, the R¹ groupsare located at the 5 and 7 positions of the pyrazolo[1,5-a]pyrimidinyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R¹ andR² each represent independently for each occurrence hydrogen or C₁₋₄alkyl.

In certain embodiments, R³ and R⁴ each represent independently for eachoccurrence hydrogen, methyl, or ethyl.

In certain embodiments, The description above describes multipleembodiments relating to compounds of Formula III. The patent applicationspecifically contemplates all combinations of the embodiments.

In certain embodiments, X¹-A¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-A¹, whereA¹ is C₃₋₁₀ cycloalkyl optionally substituted with 1 or 2 C₁₋₄ alkylgroups. In certain embodiments, X¹-A¹ is —C(O)N(H)C(H)(CF₃)-A¹, where A¹is C₃₋₁₀ cycloalkyl optionally substituted with 1 or 2 C₁₋₄ alkylgroups. In certain embodiments, X¹-A¹ is —C(O)N(H)C(C₁₋₆ alkyl)₂-R⁶-A¹,where A¹ is C₃₋₁₀ cycloalkyl optionally substituted with 1 or 2 C₁₋₄alkyl groups. In certain embodiments, X¹-A¹ is —C(O)N(H)C(CH₃)₂-A¹;where A¹ is C₃₋₁₀ cycloalkyl optionally substituted with 1 or 2 C₁₋₄alkyl groups. In certain embodiments, A¹ is cyclopropyl. In certainembodiments, A¹ is

The description above describes multiple embodiments relating tocompounds of Formula III. The patent application specificallycontemplates all combinations of the embodiments.

In certain embodiments, the substituted pyrazolo[1,5-a]pyrimidinylcarboxamide or related organic compound is a compound embraced byFormula III-1:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ and R² each represent independently for each occurrence        hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₁₋₄        haloalkoxyl, cyclopropyl, cyano, halogen, hydroxyl, —N(R⁴)₂,        —O—(C₁₋₄ alkylene)-C₁₋₆ alkoxyl, or —(C₁₋₄ alkylene)-(2-6        membered heteroalkyl optionally substituted by one or more        halogen);    -   R³ represents independently for each occurrence hydrogen, C₁₋₆        alkyl, or C₃₋₆ cycloalkyl;    -   R⁴ represents independently for each occurrence hydrogen, C₁₋₄        alkyl, cyclopropyl, or —C(O)R³;    -   X¹ is a carbonyl-containing linker selected from —C(O)N(H)(C₁₋₆        alkylene optionally substituted with C₁₋₄ alkoxyl or C₃₋₆        cycloalkyl)-ψ, —C(O)N(H)(C₁₋₆ haloalkylene)-ψ, —C(O)N(H)(C₃₋₆        cycloalkylene)-ψ, —C(O)N(H)(3-6 membered heterocycloalkylene)-ψ,        —C(O)-(3-6 membered heterocycloalkylene containing at least one        ring —N(H)— group)-ψ, and —C(O)N(H)-ψ; where ψ is a bond to A¹;    -   A¹ is a C₃₋₁₀ cycloalkyl optionally substituted with 1 or 2 C₁₋₄        alkyl groups;    -   m is 1 or 2; and    -   n is 1, 2, or 3;    -   provided that when X¹ is —C(O)N(H)-ψ and A¹ is a C₅₋₇ cycloalkyl        optionally substituted with 1 or 2 C₁₋₄ alkyl groups; then R¹ is        other than C₁₋₄ alkyl and C₁₋₄ haloalkyl.

Definitions of the variables in Formula III-1 above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii), e.g.,such as where X¹ is —C(O)N(H)(C₁₋₆ alkylene)-ψ, and R¹ and R² eachrepresent independently for each occurrence hydrogen or C₁₋₄ alkyl.

Accordingly, in certain embodiments, R¹ represents independently foreach occurrence C₁₋₄ alkyl, C₁₋₄ haloalkyl, —(C₁₋₄ alkylene)-(2-6membered heteroalkyl), cyclopropyl, halogen, or —N(R⁴)₂. In certainembodiments, R¹ represents independently for each occurrence C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, cyclopropyl, cyano, chloro, or fluoro. Incertain embodiments, R¹ is methyl.

In certain embodiments, n is 2. In certain embodiments, the R¹ groupsare located at the 5 and 7 positions of the pyrazolo[1,5-a]pyrimidinyl.

In certain embodiments, R² is hydrogen. In certain embodiments, R¹ andR² each represent independently for each occurrence hydrogen or C₁₋₄alkyl.

In certain embodiments, R³ and R⁴ each represent independently for eachoccurrence hydrogen, methyl, or ethyl.

In certain embodiments, X¹ is —C(O)N(H)(C₁₋₆ alkylene)-ψ. In certainembodiments, X¹ is —C(O)N(H)C(H)(CH₃)-ψ or —C(O)N(H)C(CH₃)₂-ψ. Incertain embodiments, X¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-ψ. In certainembodiments, X¹ is —C(O)N(H)C(H)(CF₃)-ψ. In certain embodiments, X¹ is—C(O)N(H)-ψ.

In certain embodiments, A¹ is a C₃₋₁₀ cycloalkyl optionally substitutedwith 1 or 2 C₁₋₄ alkyl groups. In certain embodiments, A¹ is a C₃₋₁₀cycloalkyl that is not substituted. In certain embodiments, A¹ is acyclopropyl. In certain embodiments, A¹ is a cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl.

The description above describes multiple embodiments relating tocompounds of Formula III-1. The patent application specificallycontemplates all combinations of the embodiments. For example, theinvention contemplates a compound of Formula III-1 wherein X¹ is—C(O)N(H)(C₁₋₆ alkylene)-ψ, and R¹ and R² each represent independentlyfor each occurrence hydrogen or C₁₋₄ alkyl.

In certain embodiments, the substituted pyrazolo[1,5-a]pyrimidinylcarboxamide or related organic compound is a compound embraced byFormula IV:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ and R² each represent independently for each occurrence        hydrogen, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ hydroxyalkyl, or C₁₋₄        cyanoalkyl;    -   R³ represents independently for each occurrence hydrogen, C₁₋₆        alkyl, or C₃₋₆ cycloalkyl;    -   R⁴ represents independently for each occurrence hydrogen, C₁₋₄        alkyl, cyclopropyl, or —C(O)R³;    -   R⁷ represents independently for each occurrence halogen,        hydroxyl, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₁₋₄        haloalkoxyl, C₃₋₆ cycloalkyl, —O—(C₃₋₆ cycloalkyl), —O—(C₁₋₆        alkylene)-C₁₋₆ alkoxyl, —O-(heteroaryl), —(C₁₋₆ alkylene)-CN,        —N(R⁴)₂, —C(O)N(R⁴)₂, 3-8 membered heterocycloalkyl, phenyl, or        heteroaryl;    -   A² is one of the following:        -   phenyl;        -   4-12 membered oxoheterocyclyl optionally substituted by 1,            2, or 3 occurrences of R⁷; or        -   6-membered heteroaryl that is (i) substituted by C₂₋₄            alkynyl and (ii) optionally substituted by 1, 2, or 3            occurrences of R⁷;    -   X¹-A¹ is as follows:        -   (i) when A² is phenyl, then X¹-A¹ is —C(O)N(H)C(H)(C₁₋₂            alkyl)-cyclopropyl, or X¹-A¹ is —C(O)N(H)(C₁₋₆            haloalkylene)-cyclopropyl;        -   (ii) when A² is a 4-12 membered oxoheterocyclyl optionally            substituted by 1, 2, or 3 occurrences of R⁷, then X¹-A¹ is            —C(O)N(H)(C₁₋₆ alkyl), —C(O)N(H)(C₁₋₆ haloalkylene)-(C₃₋₆            cycloalkyl), —C(O)N(H)(C₁₋₆ haloalkylene)-(C₁₋₆ alkyl),            —C(O)N(H)(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), or            —C(O)N(H)—(C₃₋₆ cycloalkyl); or        -   (iii) when A² is a 6-membered heteroaryl that is (i)            substituted by C₂₋₄ alkynyl and (ii) optionally substituted            by 1, 2, or 3 occurrences of R⁷, then X¹-A¹ is            —C(O)N(H)(C₁₋₆ haloalkylene)-(C₃₋₆ cycloalkyl),            —C(O)N(H)(C₁₋₆ haloalkylene)-(C₁₋₆ alkyl), or —C(O)N(H)(C₁₋₆            alkylene)-(C₃₋₆ cycloalkyl); and    -   n is 1, 2, or 3.

Definitions of the variables in Formula IV above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii).

In certain embodiments, the substituted pyrazolo[1,5-a]pyrimidinylcarboxamide or related organic compound is a compound embraced byFormula IV-A:

-   -   or a pharmaceutically acceptable salt thereof, wherein:    -   R¹ and R² each represent independently hydrogen, C₁₋₄ alkyl, or        C₁₋₄ haloalkyl;    -   R³ represents independently for each occurrence hydrogen, C₁₋₆        alkyl, or C₃₋₆ cycloalkyl;    -   R⁴ represents independently for each occurrence hydrogen, C₁₋₄        alkyl, cyclopropyl, or —C(O)R³;    -   R⁷ represents independently for each occurrence halogen,        hydroxyl, cyano, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₁₋₄        haloalkoxyl, C₃₋₆ cycloalkyl, —O—(C₃₋₆ cycloalkyl), —O—(C₁₋₆        alkylene)-C₁₋₆ alkoxyl, —O-(heteroaryl), —(C₁₋₆ alkylene)-CN,        —N(R⁴)₂, —C(O)N(R⁴)₂, 3-8 membered heterocycloalkyl, phenyl, or        heteroaryl;    -   A² is one of the following:        -   phenyl;        -   4-12 membered oxoheterocyclyl optionally substituted by 1,            2, or 3 occurrences of R⁷; or        -   6-membered heteroaryl that is (i) substituted by C₂₋₄            alkynyl and (ii) optionally substituted by 1, 2, or 3            occurrences of R⁷; and    -   X¹-A¹ is as follows:        -   (i) when A² is phenyl, then X¹-A¹ is —C(O)N(H)C(H)(C₁₋₂            alkyl)-cyclopropyl, or X¹-A¹ is —C(O)N(H)(C₁₋₆            haloalkylene)-cyclopropyl;        -   (ii) when A² is a 4-12 membered oxoheterocyclyl optionally            substituted by 1, 2, or 3 occurrences of R⁷, then X¹-A¹ is            —C(O)N(H)(C₁₋₆ alkyl), —C(O)N(H)(C₁₋₆ haloalkylene)-(C₃₋₆            cycloalkyl), —C(O)N(H)(C₁₋₆ haloalkylene)-(C₁₋₆ alkyl),            —C(O)N(H)(C₁₋₆ alkylene)-(C₃₋₆ cycloalkyl), or            —C(O)N(H)—(C₃₋₆ cycloalkyl); or        -   (iii) when A² is a 6-membered heteroaryl that is (i)            substituted by C₂₋₄ alkynyl and (ii) optionally substituted            by 1, 2, or 3 occurrences of R⁷, then X¹-A¹ is            —C(O)N(H)(C₁₋₆ haloalkylene)-(C₃₋₆ cycloalkyl),            —C(O)N(H)(C₁₋₆ haloalkylene)-(C₁₋₆ alkyl), or —C(O)N(H)(C₁₋₆            alkylene)-(C₃₋₆ cycloalkyl).

Definitions of the variables in Formula IV-A above encompass multiplechemical groups. The application contemplates embodiments where, forexample, i) the definition of a variable is a single chemical groupselected from those chemical groups set forth above, ii) the definitionis a collection of two or more of the chemical groups selected fromthose set forth above, and iii) the compound is defined by a combinationof variables in which the variables are defined by (i) or (ii).

In certain other embodiments, the compound is a compound described inthe Examples, or a pharmaceutically acceptable salt thereof. In certainother embodiments, the compound is one of the compounds listed in Table1, 2, or 3A below or a pharmaceutically acceptable salt thereof. Incertain other embodiments, the compound is one of the compounds listedin Table 3B below or a pharmaceutically acceptable salt thereof. Incertain other embodiments, the compound is one of the compounds listedin Table 1 or 2 below or a pharmaceutically acceptable salt thereof.

TABLE 1

No. R^(1-A) R^(1-B) R² X¹ A¹ I-1  2-pyridinyl ethyl H —C(O)N(H)—ψ

I-2  2-pyridinyl methyl H —C(O)N(H)—ψ

I-3  2-pyridinyl methyl H —C(O)N(H)—ψ

I-4  2-pyridinyl methyl H —C(O)N(H)—ψ

I-5  2-pyridinyl methyl H —C(O)N(H)—ψ

I-6  2-pyridinyl methyl H —C(O)N(H)—ψ

I-7  2-pyridinyl methyl H —C(O)N(H)—ψ

I-8  2-thiophenyl methyl H —C(O)N(H)—ψ

I-9  2-furanyl methyl H —C(O)N(H)—ψ

I-10 4-tetrahydropyranyl methyl —C(O)N(H)—ψ

I-11 4-tetrahydropyranyl methyl H —C(O)N(H)—ψ

I-12 4-tetrahydropyranyl methyl H —C(O)N(H)—ψ

I-13 3-pyridinyl methyl H —C(O)N(H)(CH₂)₂—ψ

I-14 3-pyridinyl methyl H —C(O)N(H)(CH₂)₂—ψ

I-15 3-pyridinyl methyl H —C(O)N(H)(CH₂)₂—ψ

I-16 3-pyridinyl methyl H —C(O)N(H)(CH₂)₂—ψ

I-17 3-pyridinyl methyl H —C(O)N(H)(CH₂)₂—ψ

I-18 3-pyridinyl methyl H —C(O)N(H)(CH₂)₂—ψ

I-19 3-pyridinyl methyl H —C(O)N(H)(CH₂)₂—ψ

I-20 3-pyridinyl methyl H —C(O)N(H)(CH₂)₂—ψ

I-21 3-pyridinyl methyl H —C(O)N(H)(CH₂)₂—ψ cyclopropyl I-22 3-pyridinylmethyl H —C(O)N(H)C(H)(CF₃)—ψ 2-thiophenyl I-23 4-piperidinyl methyl H—C(O)N(H)C(H)(CF₃)—ψ

I-24 4-piperidinyl methyl H —C(O)N(H)C(H)(CF₃)—ψ 2-thiophenyl I-25—C(Me)₂CN methyl H —C(O)N(H)C(H)(CF₃)—ψ cyclopropyl I-26 —C(Me)₂OHmethyl H —C(O)N(H)C(H)(CF₃)—ψ cyclopropyl I-27 Cl methyl H—C(O)N(H)C(H)(CF₃)—ψ 2-furanyl I-28 Cl methyl H —C(O)N(H)C(H)(CF₃)—ψ

I-29 methyl CN H —C(O)N(H)C(H)(CF₃)—ψ

I-30 methyl CN H —C(O)N(H)C(H)(CF₃)—ψ cyclopropylWhere in Table 1, ψ is a bond to A¹.

TABLE 2 Compound No. Compound Structure II-1 

II-2 

II-3 

II-4 

II-5 

II-6 

II-8 

II-9 

II-10

Methods for preparing compounds described herein are illustrated in thefollowing synthetic schemes. These schemes are given for the purpose ofillustrating the invention, and should not be regarded in any manner aslimiting the scope or the spirit of the invention. Starting materialsshown in the schemes can be obtained from commercial sources or can beprepared based on procedures described in the literature.

The synthetic route illustrated in Scheme 1 depicts an exemplaryprocedure for preparing substituted pyrazolo[1,5-a]pyrimidine compounds.In the first step, ethyl 5-amino-1H-pyrazole-4-carboxylate (R^(i)═H) Ais condensed with ethyl (E)-3-ethoxybut-2-enoate (R^(ii)═H, R^(iii)=Me)in DMF at Cs₂CO₃ to afford ethyl5-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate B. Heating ofcarboxylate B with phosphoryl trichloride affords the intermediate ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate C. Hydrolysisof chloro ester C under basic conditions provides ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid D.

Carboxylic acid D can be treated with a variety of substituted aromaticor aliphatic amines using standard peptide coupling procedures, such asHATU and/or HOBT in DMF in the presence of DIPEA to afford chloro amideG. In the final step, Pd-catalyzed coupling of chloro amide G with avariety of aromatic or heteraromatic boronic acids or esters or withtrialkylstannyl reagents may be accomplished using standard Pd-catalyzedcoupling procedures such as Suzuki and Buchwald coupling. For example,using Suzuki coupling conditions (such as Pd(dppf)₂Cl₂.CH₂Cl₂ in DME inthe presence of K₃PO₄) affords substituted amide H. In some cases,substitution of the chloro amide G with a primary or secondary amineaffords the substituted amide H.

Alternatively chloro carboxylic ester C can undergo Pd-catalyzedcoupling with a variety of aromatic/heteraromatic boronic acids oresters or with trialkylstannyl reagents using standard Pd-catalyzedcoupling procedures such as Suzuki and Buchwald coupling. For example,using Suzuki coupling conditions (such as Pd(dppf)₂Cl₂.CH₂Cl₂ in DME inthe presence of K₃PO₄) affords substituted carboxylic ester E.Alternatively, substitution of the chloro carboxylic ester C with aprimary or secondary amine affords the substituted carboxylic ester E.Hydrolysis of carboxylic ester E under basic or neutral conditionsaffords carboxylic acid F. In the final step, coupling of carboxylicacid F with a variety of substituted aromatic or aliphatic amines may beaccomplished using standard peptide coupling procedures, such as HATUand/or HOBT in DMF in the presence of DIPEA to afford amide H.

The reaction procedures in Scheme 1 are contemplated to be amenable topreparing a wide variety of substituted pyrazolo[1,5-a]pyrimidinecarboxamide compounds having different substituents at the A¹ and Y¹positions. Furthermore, if a functional group that is part of the A¹and/or Y¹ would not be amenable to a reaction condition described inScheme 1, it is contemplated that the functional group can first beprotected using standard protecting group chemistry and strategies, andthen the protecting group is removed after completing the desiredsynthetic transformation. See, for example, Greene, T. W.; Wuts, P. G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: New York,1991, for further description of protecting chemistry and strategies. Incertain other embodiments, a functional group in substituent A¹ and Y¹can converted to another functional group using standard functionalgroup manipulation procedures known in the art. See, for example,“Comprehensive Organic Synthesis” (B. M. Trost & I. Fleming, eds.,1991-1992).

III. Therapeutic Applications

The invention provides methods of treating medical disorders, such asGaucher disease, Parkinson's disease, Lewy body disease, dementia,multiple system atrophy, epilepsy, bipolar disorder, schizophrenia, ananxiety disorder, major depression, polycystic kidney disease, type 2diabetes, open angle glaucoma, multiple sclerosis, endometriosis, andmultiple myeloma, using the substituted pyrazolo[1,5-a]pyrimidinylcarboxamide, related compounds, and pharmaceutical compositionsdescribed herein. Treatment methods include the use of substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide or related organic compoundsdescribed herein as stand-alone therapeutic agents and/or as part of acombination therapy with another therapeutic agent. Although not wishingto be bound by a particular theory, it is understood that substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide and related organic compoundsdescribed herein may activate glucocerebrosidase (Gcase).

Methods of Treating Medical Disorders

One aspect of the invention provides a method of treating disorderselected from the group consisting of Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, multiple system atrophy, epilepsy,bipolar disorder, schizophrenia, an anxiety disorder, major depression,polycystic kidney disease, type 2 diabetes, open angle glaucoma,multiple sclerosis, endometriosis, and multiple myeloma. The methodcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a substituted pyrazolo[1,5-a]pyrimidinyl carboxamideor related organic compound described herein to treat the disorder. Thecompound may be a compound of Formula I, I-1, I-A, II, II-A, III, III-1,or IV described above in Section II.

In certain embodiments, the compound is a compound of Formula I. Incertain embodiments, the compound is a compound of Formula II. Incertain embodiments, the compound is a compound of Formula III.

In certain embodiments, the disorder is Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, or multiple system atrophy. Incertain embodiments, the disorder is Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, or multiple system atrophy. Incertain other embodiments, the disorder is Gaucher disease. In certainembodiments, the disorder is Parkinson's disease. In certainembodiments, the disorder is Lewy body disease. In certain embodiments,the disorder is dementia. In certain embodiments, the disorder is adementia selected from the group consisting of Alzheimer's disease,frontotemporal dementia, and a Lewy body variant of Alzheimer's disease.In certain embodiments, the disorder is multiple system atrophy.

In certain embodiments, the disorder is an anxiety disorder, such aspanic disorder, social anxiety disorder, or generalized anxietydisorder.

Efficacy of the compounds in treating Gaucher disease, Parkinson'sdisease, Lewy body disease, dementia, multiple system atrophy, epilepsy,bipolar disorder, schizophrenia, an anxiety disorder, major depression,polycystic kidney disease, type 2 diabetes, open angle glaucoma,multiple sclerosis, endometriosis, and multiple myeloma may be evaluatedby testing the compounds in assays known in the art for evaluatingefficacy against these diseases and/or, e.g., for activation ofglucocerebrosidase (Gcase), as discussed in the Examples below.

In certain embodiments, the patient is a human.

In certain embodiments, the compound is one of the generic or specificcompounds described in Section II, such as a compound of Formula I, acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I, a compound of FormulaI-A, or a compound embraced by one of the further embodiments describingdefinitions for certain variables of Formula I-A. In certain otherembodiments, the compound is a compound of Formula II or II-A or acompound embraced by one of the further embodiments describingdefinitions for certain variables of Formula II or II-A.

The description above describes multiple embodiments relating to methodsof treating various disorders using certain substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide or related organic compounds. Thepatent application specifically contemplates all combinations of theembodiments. For example, the invention contemplates methods fortreating Gaucher disease, Parkinson's disease, Lewy body disease,dementia, or multiple system atrophy by administering a therapeuticallyeffective amount of a compound of Formula I-A.

Medical Use and Preparation of Medicament

Another aspect of the invention relates to compounds and compositionsdescribed herein for use in treating a disorder described herein.Another aspect of the invention pertains to use of a compound orcomposition described herein in the preparation of a medicament fortreating a disorder described herein.

Combination Therapy

The invention embraces combination therapy, which includes theadministration of a substituted pyrazolo[1,5-a]pyrimidinyl carboxamideor related compound described herein (such as compound of Formula I,I-1, I-A, II, II-A, III, III-1, or IV) and a second agent as part of aspecific treatment regimen intended to provide the beneficial effectfrom the co-action of these therapeutic agents. The beneficial effect ofthe combination may include pharmacokinetic or pharmacodynamic co-actionresulting from the combination of therapeutic agents.

Exemplary second agents for use in treating Gaucher disease include, forexample, taliglucerase alfa, velaglucerase alfa, eliglustat, andmiglustat. Exemplary second agents for use in treating Parkinson'sdisease include, for example, a glucosylceramide synthase inhibitor(e.g., ibiglustat), an acid ceramidase inhibitor (e.g., carmofur), anacid sphingomyelinase activator, levodopa, pramipexole, ropinirole,rotigotine, apomorphine, or salt thereof. Additional glucosylceramidesynthase inhibitors for use in combination therapies include, forexample, those described in International Patent ApplicationPublications WO 2015/089067, WO 2014/151291, WO 2014/043068, WO2008/150486, WO 2010/014554, WO 2012/129084, WO 2011/133915, and WO2010/091164; U.S. Pat. No. 9,126,993, U.S. Pat. No. 8,961,959, U.S. Pat.No. 8,940,776, U.S. Pat. No. 8,729,075, and U.S. Pat. No. 8,309,593; andU.S. Patent Application Publications US 2014/0255381 and US2014/0336174; each of which are hereby incorporated by reference.Additional acid ceramidase inhibitors for use in combination therapiesinclude, for example, those described in International PatentApplication Publications WO 2015/173168 and WO 2015/173169, each ofwhich are hereby incorporated by reference.

IV. Pharmaceutical Compositions

The invention provides pharmaceutical compositions comprising asubstituted pyrazolo[1,5-a]pyrimidinyl carboxamide or related organiccompound described herein, such as a compound of Formula I, I-1, I-A,II, II-A, III, III-1, or IV. In certain embodiments, the pharmaceuticalcompositions preferably comprise a therapeutically-effective amount ofone or more of the substituted pyrazolo[1,5-a]pyrimidinyl carboxamide orrelated organic compounds described above, formulated together with oneor more pharmaceutically acceptable carriers (additives) and/ordiluents. As described in detail below, the pharmaceutical compositionsof the present invention may be specially formulated for administrationin solid or liquid form, including those adapted for the following: (1)oral administration, for example, drenches (aqueous or non-aqueoussolutions or suspensions), tablets (e.g., those targeted for buccal,sublingual, and/or systemic absorption), boluses, powders, granules,pastes for application to the tongue; (2) parenteral administration by,for example, subcutaneous, intramuscular, intravenous or epiduralinjection as, for example, a sterile solution or suspension, orsustained-release formulation; (3) topical application, for example, asa cream, ointment, or a controlled-release patch or spray applied to theskin; (4) intravaginally or intrarectally, for example, as a pessary,cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8)nasally.

The phrase “therapeutically-effective amount” as used herein means thatamount of a compound, material, or composition comprising a compound ofthe present invention which is effective for producing some desiredtherapeutic effect in at least a sub-population of cells in an animal ata reasonable benefit/risk ratio applicable to any medical treatment.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

Wetting agents, emulsifiers and lubricants, such as sodium laurylsulfate and magnesium stearate, as well as coloring agents, releaseagents, coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the compositions.

Examples of pharmaceutically-acceptable antioxidants include: (1) watersoluble antioxidants, such as ascorbic acid, cysteine hydrochloride,sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2)oil-soluble antioxidants, such as ascorbyl palmitate, butylatedhydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propylgallate, alpha-tocopherol, and the like; and (3) metal chelating agents,such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol,tartaric acid, phosphoric acid, and the like.

Formulations of the present invention include those suitable for oral,nasal, topical (including buccal and sublingual), rectal, vaginal and/orparenteral administration. The formulations may conveniently bepresented in unit dosage form and may be prepared by any methods wellknown in the art of pharmacy. The amount of active ingredient which canbe combined with a carrier material to produce a single dosage form willvary depending upon the host being treated, the particular mode ofadministration.

The amount of active ingredient which can be combined with a carriermaterial to produce a single dosage form will generally be that amountof the compound which produces a therapeutic effect. Generally, out ofone hundred percent, this amount will range from about 0.1 percent toabout ninety-nine percent of active ingredient, preferably from about 5percent to about 70 percent, most preferably from about 10 percent toabout 30 percent.

In certain embodiments, a formulation of the present invention comprisesan excipient selected from the group consisting of cyclodextrins,celluloses, liposomes, micelle forming agents, e.g., bile acids, andpolymeric carriers, e.g., polyesters and polyanhydrides; and a compoundof the present invention. In certain embodiments, an aforementionedformulation renders orally bioavailable a compound of the presentinvention.

Methods of preparing these formulations or compositions include the stepof bringing into association a compound of the present invention withthe carrier and, optionally, one or more accessory ingredients. Ingeneral, the formulations are prepared by uniformly and intimatelybringing into association a compound of the present invention withliquid carriers, or finely divided solid carriers, or both, and then, ifnecessary, shaping the product.

Formulations of the invention suitable for oral administration may be inthe form of capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, or as a solution or a suspension in an aqueous or non-aqueousliquid, or as an oil-in-water or water-in-oil liquid emulsion, or as anelixir or syrup, or as pastilles (using an inert base, such as gelatinand glycerin, or sucrose and acacia) and/or as mouth washes and thelike, each containing a predetermined amount of a compound of thepresent invention as an active ingredient. A compound of the presentinvention may also be administered as a bolus, electuary or paste.

In solid dosage forms of the invention for oral administration(capsules, tablets, pills, dragees, powders, granules, trouches and thelike), the active ingredient is mixed with one or morepharmaceutically-acceptable carriers, such as sodium citrate ordicalcium phosphate, and/or any of the following: (1) fillers orextenders, such as starches, lactose, sucrose, glucose, mannitol, and/orsilicic acid; (2) binders, such as, for example, carboxymethylcellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3)humectants, such as glycerol; (4) disintegrating agents, such asagar-agar, calcium carbonate, potato or tapioca starch, alginic acid,certain silicates, and sodium carbonate; (5) solution retarding agents,such as paraffin; (6) absorption accelerators, such as quaternaryammonium compounds and surfactants, such as poloxamer and sodium laurylsulfate; (7) wetting agents, such as, for example, cetyl alcohol,glycerol monostearate, and non-ionic surfactants; (8) absorbents, suchas kaolin and bentonite clay; (9) lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, zinc stearate, sodium stearate, stearic acid, and mixturesthereof; (10) coloring agents; and (11) controlled release agents suchas crospovidone or ethyl cellulose. In the case of capsules, tablets andpills, the pharmaceutical compositions may also comprise bufferingagents. Solid compositions of a similar type may also be employed asfillers in soft and hard-shelled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

A tablet may be made by compression or molding, optionally with one ormore accessory ingredients. Compressed tablets may be prepared usingbinder (for example, gelatin or hydroxypropylmethyl cellulose),lubricant, inert diluent, preservative, disintegrant (for example,sodium starch glycolate or cross-linked sodium carboxymethyl cellulose),surface-active or dispersing agent. Molded tablets may be made bymolding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be formulated for rapid release,e.g., freeze-dried. They may be sterilized by, for example, filtrationthrough a bacteria-retaining filter, or by incorporating sterilizingagents in the form of sterile solid compositions which can be dissolvedin sterile water, or some other sterile injectable medium immediatelybefore use. These compositions may also optionally contain opacifyingagents and may be of a composition that they release the activeingredient(s) only, or preferentially, in a certain portion of thegastrointestinal tract, optionally, in a delayed manner. Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

Liquid dosage forms for oral administration of the compounds of theinvention include pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. In addition to the activeingredient, the liquid dosage forms may contain inert diluents commonlyused in the art, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, coloring, perfuming and preservative agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, and mixturesthereof.

Formulations of the pharmaceutical compositions of the invention forrectal or vaginal administration may be presented as a suppository,which may be prepared by mixing one or more compounds of the inventionwith one or more suitable nonirritating excipients or carrierscomprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the rectumor vaginal cavity and release the active compound.

Formulations of the present invention which are suitable for vaginaladministration also include pessaries, tampons, creams, gels, pastes,foams or spray formulations containing such carriers as are known in theart to be appropriate.

Dosage forms for the topical or transdermal administration of a compoundof this invention include powders, sprays, ointments, pastes, creams,lotions, gels, solutions, patches and inhalants. The active compound maybe mixed under sterile conditions with a pharmaceutically-acceptablecarrier, and with any preservatives, buffers, or propellants which maybe required.

The ointments, pastes, creams and gels may contain, in addition to anactive compound of this invention, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to a compound of thisinvention, excipients such as lactose, talc, silicic acid, aluminumhydroxide, calcium silicates and polyamide powder, or mixtures of thesesubstances. Sprays can additionally contain customary propellants, suchas chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons,such as butane and propane.

Transdermal patches have the added advantage of providing controlleddelivery of a compound of the present invention to the body. Such dosageforms can be made by dissolving or dispersing the compound in the propermedium. Absorption enhancers can also be used to increase the flux ofthe compound across the skin. The rate of such flux can be controlled byeither providing a rate controlling membrane or dispersing the compoundin a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like,are also contemplated as being within the scope of this invention.

Pharmaceutical compositions of this invention suitable for parenteraladministration comprise one or more compounds of the invention incombination with one or more pharmaceutically-acceptable sterileisotonic aqueous or nonaqueous solutions, dispersions, suspensions oremulsions, or sterile powders which may be reconstituted into sterileinjectable solutions or dispersions just prior to use, which may containsugars, alcohols, antioxidants, buffers, bacteriostats, solutes whichrender the formulation isotonic with the blood of the intended recipientor suspending or thickening agents.

Examples of suitable aqueous and nonaqueous carriers which may beemployed in the pharmaceutical compositions of the invention includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), and suitable mixtures thereof,vegetable oils, such as olive oil, and injectable organic esters, suchas ethyl oleate. Proper fluidity can be maintained, for example, by theuse of coating materials, such as lecithin, by the maintenance of therequired particle size in the case of dispersions, and by the use ofsurfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms upon the subject compounds may be ensuredby the inclusion of various antibacterial and antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like into the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is desirableto slow the absorption of the drug from subcutaneous or intramuscularinjection. This may be accomplished by the use of a liquid suspension ofcrystalline or amorphous material having poor water solubility. The rateof absorption of the drug then depends upon its rate of dissolutionwhich, in turn, may depend upon crystal size and crystalline form.Alternatively, delayed absorption of a parenterally-administered drugform is accomplished by dissolving or suspending the drug in an oilvehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe subject compounds in biodegradable polymers such aspolylactide-polyglycolide. Depending on the ratio of drug to polymer,and the nature of the particular polymer employed, the rate of drugrelease can be controlled. Examples of other biodegradable polymersinclude poly(orthoesters) and poly(anhydrides). Depot injectableformulations are also prepared by entrapping the drug in liposomes ormicroemulsions which are compatible with body tissue.

When the compounds of the present invention are administered aspharmaceuticals, to humans and animals, they can be given per se or as apharmaceutical composition containing, for example, 0.1 to 99% (morepreferably, 10 to 30%) of active ingredient in combination with apharmaceutically acceptable carrier.

The preparations of the present invention may be given orally,parenterally, topically, or rectally. They are of course given in formssuitable for each administration route. For example, they areadministered in tablets or capsule form, by injection, inhalation, eyelotion, ointment, suppository, etc. administration by injection,infusion or inhalation; topical by lotion or ointment; and rectal bysuppositories. Oral administrations are preferred.

The phrases “parenteral administration” and “administered parenterally”as used herein means modes of administration other than enteral andtopical administration, usually by injection, and includes, withoutlimitation, intravenous, intramuscular, intraarterial, intrathecal,intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal,transtracheal, subcutaneous, subcuticular, intraarticulare, subcapsular,subarachnoid, intraspinal and intrasternal injection and infusion.

The phrases “systemic administration,” “administered systemically,”“peripheral administration” and “administered peripherally” as usedherein mean the administration of a compound, drug or other materialother than directly into the central nervous system, such that it entersthe patient's system and, thus, is subject to metabolism and other likeprocesses, for example, subcutaneous administration.

These compounds may be administered to humans and other animals fortherapy by any suitable route of administration, including orally,nasally, as by, for example, a spray, rectally, intravaginally,parenterally, intracisternally and topically, as by powders, ointmentsor drops, including buccally and sublingually.

Regardless of the route of administration selected, the compounds of thepresent invention, which may be used in a suitable hydrated form, and/orthe pharmaceutical compositions of the present invention, are formulatedinto pharmaceutically-acceptable dosage forms by conventional methodsknown to those of skill in the art.

Actual dosage levels of the active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active ingredient which is effective to achieve the desiredtherapeutic response for a particular patient, composition, and mode ofadministration, without being toxic to the patient.

The selected dosage level will depend upon a variety of factorsincluding the activity of the particular compound of the presentinvention employed, or the ester, salt or amide thereof, the route ofadministration, the time of administration, the rate of excretion ormetabolism of the particular compound being employed, the rate andextent of absorption, the duration of the treatment, other drugs,compounds and/or materials used in combination with the particularcompound employed, the age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell known in the medical arts.

A physician or veterinarian having ordinary skill in the art can readilydetermine and prescribe the effective amount of the pharmaceuticalcomposition required. For example, the physician or veterinarian couldstart doses of the compounds of the invention employed in thepharmaceutical composition at levels lower than that required in orderto achieve the desired therapeutic effect and gradually increase thedosage until the desired effect is achieved.

In general, a suitable daily dose of a compound of the invention will bethat amount of the compound which is the lowest dose effective toproduce a therapeutic effect. Such an effective dose will generallydepend upon the factors described above. Preferably, the compounds areadministered at about 0.01 mg/kg to about 200 mg/kg, more preferably atabout 0.1 mg/kg to about 100 mg/kg, even more preferably at about 0.5mg/kg to about 50 mg/kg. When the compounds described herein areco-administered with another agent (e.g., as sensitizing agents), theeffective amount may be less than when the agent is used alone.

If desired, the effective daily dose of the active compound may beadministered as two, three, four, five, six or more sub-dosesadministered separately at appropriate intervals throughout the day,optionally, in unit dosage forms. Preferred dosing is one administrationper day.

V. Kits for Use in Medical Applications

Another aspect of the invention provides a kit for treating a disorder.The kit comprises: i) instructions for treating a medical disorder, suchas Gaucher disease, Parkinson's disease, Lewy body disease, dementia, ormultiple system atrophy; and ii) a substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide or related organic compounddescribed herein, such as a compound of Formula I, I-1, I-A, II, II-A,III, III-1, or IV. The kit may comprise one or more unit dosage formscontaining an amount of a substituted pyrazolo[1,5-a]pyrimidinylcarboxamide or related organic compound described herein, such as acompound of Formula I, that is effective for treating said medicaldisorder, e.g., Gaucher disease, Parkinson's disease, Lewy body disease,dementia, or multiple system atrophy.

The description above describes multiple aspects and embodiments of theinvention, including substituted pyrazolo[1,5-a]pyrimidinyl carboxamideand related organic compounds, compositions comprising a substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide or related organic compounds,methods of using the substituted pyrazolo[1,5-a]pyrimidinyl carboxamideor related organic compounds, and kits. The patent applicationspecifically contemplates all combinations and permutations of theaspects and embodiments. For example, the invention contemplatestreating Gaucher disease, Parkinson's disease, Lewy body disease,dementia, or multiple system atrophy in a human patient by administeringa therapeutically effective amount of a compound of Formula I-A.Further, for example, the invention contemplates a kit for treatingGaucher disease, Parkinson's disease, Lewy body disease, dementia, ormultiple system atrophy, the kit comprising instructions for treatingGaucher disease, Parkinson's disease, Lewy body disease, dementia, ormultiple system atrophy and ii) a substituted pyrazolo[1,5-a]pyrimidinylcarboxamide or related organic compound described herein, such as acompound of Formula I-A.

EXAMPLES

The invention now being generally described, will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.

Example 1—Preparation of Pyrazolo[1,5-a]Pyrimidinyl CarboxamideCompounds

Pyrazolo[1,5-a]pyrimidine-3-carboxamide compounds were prepared based onthe general procedures described in Part I below. Exemplary proceduresfor preparing specific amine compounds useful as synthetic intermediatesin the preparation of certain pyrazolo[1,5-a]pyrimidine-3-carboxamidecompounds are provided in Part II below. Exemplary procedures forpreparing specific carboxylic acid compounds useful as syntheticintermediates in the preparation of certainpyrazolo[1,5-a]pyrimidine-3-carboxamide compounds are provided in PartIII below. Specific pyrazolo[1,5-a]pyrimidine-3-carboxamide compoundsprepared according to the general procedures are provided in Part IVbelow.

Part I—General Procedures

General Procedure A: Preparation of Amide by Coupling of a CarboxylicAcid Compound with an Amine Compound

To a stirred solution of carboxylic acid compound (1.0 equivalent), HATU(1.5 equivalents), and DIPEA (3.75 equivalents) in DCM or DMF (˜4 mL/0.2mmol) was added amine compound (1.25-2.0 equivalents). The reactionmixture was stirred at RT for 4-16 h, and then washed with saturatedaqueous NaHCO₃ solution (5 mL/0.2 mmol), aqueous citric acid solution (5mL/0.2 mmol) and brine (5 mL/0.2 mmol). The combined extracts were driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The resultingcrude material was purified by silica gel column chromatography orpreparatory HPLC to give the amide compound.

General Procedure B: Conversion of Carboxylic Ester Compound toCarboxylic Acid Compound

To a solution of carboxylic ester (1.0 equivalent) in EtOH (5.0 mL/1.0mmol) and water (0-3.0 mL/1.0 mmol) was added NaOH (2.0-5.0 equivalents)and the mixture was heated at 80° C. for 2 h and then concentrated. Tothe concentrate, 6N HCl solution was added to adjust the pH to 5-6 andthen the mixture was stirred for 10 minutes and subsequently filtered.The resulting solid was collected and dried to give the carboxylic acidcompound.

General Procedure B*: Conversion of Carboxylic Ester Compound toCarboxylic Acid Compound

To a solution of carboxylic ester (1.0 equivalent) in EtOH (5.0 mL/1.0mmol) and water (0-3.0 mL/1.0 mmol) was added NaOH (2.0-5.0 equivalents)and the mixture was heated at 80° C. for 2 h and then concentrated. Tothe concentrate, 6N HCl solution was added to adjust the pH to 5˜6 andthen the mixture was stirred for 10 minutes and subsequently filtered.The resulting solid was collected and dried to give the carboxylic acidcompound.

Alternatively, to a solution of carboxylic ester (1.0 equivalent) in THF(5.0 mL/1.0 mmol) was added LiOH (1M solution, 3 equivalents) and themixture was stirred at 60° C. for 1-2 h and then the pH was adjusted to˜7 with 1 N HCl. The resulting solution was lyophilized to afford thecrude carboxylic acid.

General Procedure C: Preparation of Amide from a Carboxylic AcidCompound and Amine Compound

To a solution of carboxylic acid compound (1.0 equivalent) in DCM (3mL/0.5 mmol) was added DMF (1 drop) and oxalyl chloride (2.0equivalents). The solution was stirred at RT for 30 minutes and thenconcentrated in vacuo. The resulting residue was dissolved in DCM (1mL/0.5 mmol) followed by the addition of amine compound (5.0equivalents) and triethylamine (2.0 equivalents). The reaction mixturewas stirred at RT for 2 h and then diluted with DCM (10 mL/0.5 mmol).The organic solution was washed sequentially with H₂O (10 mL/0.5 mmol)and brine (10 mL/0.5 mmol), then dried over anhydrous Na₂SO₄, and nextfiltered. The filtrate was concentrated in vacuo, and the resultingresidue was purified by preparatory HPLC or silica gel chromatography togive the amide compound.

General Procedure D: Preparation of Coupled Aryl and Heteroaryl GroupsUsing Suzuki Catalyzed Coupling Conditions Between an Organoboronic Acidor Ester and an Aryl Halide or Heteroaryl Halide

A suspension of heteroaryl chloride (1 equivalent), organoboronic acidor organoboronic ester (1.2 equivalents), K₃PO₄ (3.0 equivalents), andPd(dppf)Cl₂.DCM (5 mol %) or Pd₂(dba)₃ (10 mol %) in DME or 1,4-dioxane(40 mL/mmol) was stirred at 70-100° C. for 2-6 hours under N₂. Then, thereaction mixture was concentrated in vacuo and the resulting residuepurified by silica gel column chromatography to afford the coupled ringsystem.

General Procedure E: Preparation of Coupled Aryl and Heteroaryl GroupsUsing Buchwald Catalyzed Coupling Conditions Between an Organohalide inthe Presence of a Tin Reagent

A solution of organobromide (1.0 equivalent), organochloride (1.0equivalent), hexabutylditin (1.0 equivalent), and Pd(dppf)Cl₂.DCM (10mol %) in anhydrous 1,4-dioxane (10 mL/mmol) was stirred at 100° C.under N₂ overnight, then cooled and the reaction quenched with water (20mL/mmol). The resulting mixture was extracted with EtOAc (20 mL/mmol×3),the organic phases were separated and dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo, and the resultingresidue was purified by silica gel column chromatography orpreparative-TLC to afford the coupled ring system.

General Procedure E*: Preparation of Coupled Aryl and Heteroaryl GroupsUsing Buchwald Catalyzed Coupling Conditions Between an Organohalide inthe Presence of a Tin Reagent

A solution of organobromide (1.0 equivalent), organochloride (1.0equivalent), hexabutylditin (1.0 equivalent), and Pd(dppf)Cl₂.DCM orPd(t-Bu₃P)₂ (10 mol %) in anhydrous 1,4-dioxane (10 mL/mmol) was stirredat 100° C. under N₂ overnight, then cooled and the reaction was quenchedwith water (20 mL/mmol). The resulting mixture was extracted with EtOAc(20 mL/mmol×3), then the organic phases were separated and dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo,and the resulting residue was purified by silica gel columnchromatography or preparative TLC to afford the coupled ring system.

General Procedure F: Preparation of Coupled Aryl and Heteroaryl GroupsUsing Buchwald Catalyzed Coupling Conditions Between an Organohalide andOrganotin Reagent

A solution of organochloride (1.0 equivalent) and organotin reagent (1.0equivalent) in 1,4-dioxane (20 mL/mmol) was stirred and purged with N₂three times at RT. Then Pd(dppf)Cl₂.DCM (10 mol %) was quickly addedunder a N₂ atmosphere to the reaction mixture, followed by additionalpurging with N₂ (×3) and then the mixture was stirred at 120° C.overnight. Next, the reaction was cooled to RT and then quenched withwater (20 mL/mmol). The resulting mixture was extracted with EA (20mL/mmol×3), and the organic phases were dried over anhydrous Na₂SO₄ andfiltered and concentrated in vacuo. The resulting residue was purifiedby silica gel column chromatography or preparative-TLC to afford thecoupled ring system.

General Procedure G: Preparation of a Heteroaryl Amine UsingSubstitution Between an Organohalide and Aliphatic Amine

A solution of organochloride (1.0 equivalent), amine hydrochloride (1.3equivalent) and DIEA (3.0 equivalents) in DMF (5 mL/1 mmol) was stirredat 60° C. for 5 h, then cooled to RT and diluted with EA (30 mL/mmol).The resulting mixture was washed with H₂O (10 mL/mmol×3) and the organicphases were dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo, and the resulting residue was purified by silicagel column chromatography to afford the amine compound.

General Procedure H: Preparation of Coupled Imidazolidinyl Groups UsingBuchwald Catalyzed Coupling Conditions Between an Organohalide andImidazolidinyl Reagent

A solution of organochloride (1.0 equivalent), imidazolidinyl reagent(1.0-2.0 equivalents), Pd₂(dba)₃ (10 mol %), x-antphos (20 mol %) andCs₂CO₃ (2.1 equivalents) in dioxane (0.3 mmol/5 mL) was stirred at 110°C. for 2-16 h under a N₂ atmosphere. The reaction mixture was thencooled to RT, quenched with saturated NH₄Cl (20 mL), and extracted withEA (30 mL×3). The combined organic layers were washed with brine (30mL), dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo, and the resulting residue was purified by silicagel column chromatography to afford the coupled ring system.

Part II—Preparation of Specific Amine Compounds

Exemplary procedures for preparing specific amine compounds useful inthe preparation of certain pyrazolo[1,5-a]pyrimidine-3-carboxamidecompounds are provided below.

2-Cyclopropylpropan-2-amine

To a solution of 1-cyclopropylethan-1-one (1.0 g, 11.2 mmol) inanhydrous Et₂O (5 mL) was added a solution of MgMeBr (4.4 mL, 13.2 mmol)at a rate suitable to maintain gentle reflux of the solvent, to affordthe expected alcoholate as a white precipitate. The reaction mixture wasmaintained refluxing for an additional 30 minutes, then stirred at RTovernight, and quenched with sat. NH₄Cl solution (5 mL). The resultingmixture was extracted with Et₂O (5 mL), and the combined organic layerswere washed with brine (5 mL), dried over Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo to afford 2-cyclopropylpropan-2-ol asa pale yellow oil (1.1 g, 92%). ¹H NMR (500 MHz, CDCl₃) δ 1.18 (s, 6H),0.97-0.94 (m, 1H), 0.39-0.30 (m, 4H).

To a stirred solution of 2-cyclopropylpropan-2-ol (1.1 g, 11.2 mmol) inCHCl₃ (10 mL) was added NaN₃ (1.08 g, 15.8 mmol) and Cl₃CO₂H (2.8 g,17.2 mmol) successively at RT. The mixture was stirred at RT for 2 h,washed with two portions of 10% aqueous NaHCO₃ solution (5 mL), brine(10 mL), dried over Na₂SO₄ and filtered. The filtrate was concentratedin vacuo to afford (2-azidopropan-2-yl)cyclopropane as a clear oil (1.2g, 85%).

To a suspension of LiAlH₄ (670 mg, 17.7 mmol) in anhydrous diethyl ether(6 mL) was added a solution of (2-azidopropan-2-yl)cyclopropane (1.2 g,11.2 mmol) in 4 mL of anhydrous diethyl ether at a rate such that refluxwas maintained. After refluxing for 2 h, the reaction mixture was cooledto 0° C., quenched by careful addition of 0.67 mL of H₂O, 0.67 mL of 15%NaOH solution, and 2.0 mL of H₂O, successively. The solid was filteredoff and the filtrate was concentrated in vacuo to afford2-cyclopropylpropan-2-amine as a clear oil (1.0 g, 90%).

[1,1′-Bi(cyclopropan)]-1-amine

To a solution of cyclopropanecarbonitrile (1.0 g, 15 mmol) in diethylether (15 mL) was added Ti(OiPr)₄ (4.66 g, 16.4 mmol) and the solutionwas cooled to −78° C. and EtMgBr solution (3 M in ether, 30 mmol) wasslowly added. After 10 minutes at −78° C., the slurry was allowed towarm up to RT and stirred for 1 h. BF₃.OEt₂ (4.26 g, 30 mmol) was addedand the mixture was stirred at RT for 18 h. To this mixture, 2N NaOH (30mL) was slowly added at 0° C. The organic phase was separated andextracted with 2N HCl (30 mL). The aqueous phase was concentrated invacuo and the resulting residue was triturated in diethyl ether toafford [1,1′-bi(cyclopropan)]-1-amine (0.5 g, 34%) as the hydrochloridesalt.

1-Cyclopropyl-3-methylbutan-1-amine

A mixture of cyclopropanecarbonitrile (5.0 g, 74.6 mmol) and iBuMgBr(326 mg, 2.4 mmol) in diethyl ether (10 mL) was stirred at reflux for 5h, quenched with sat. NH₄Cl solution (10 mL) and extracted with EtOAc(10 mL×3). The combined organic layers were dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated in vacuo to give crude imine(7.5 g, 80%), which was used directly in the next step. A mixture ofimine (7.5 g, 60 mmol) and NaBH₄ (2.28 g, 60 mmol) in MeOH (50 mL) wasstirred at RT for 3 h, quenched with water (50 mL) and extracted withEtOAc (50 mL×3). The organic layers were dried over anhydrous Na₂SO₄,and filtered. The filtrate was concentrated in vacuo, and the resultingresidue was dissolved in HCl/dioxane (50 mL, 4M). The resulting mixturewas stirred at RT for 30 min and concentrated in vacuo. Diethyl ether(50 mL) was added resulting in a precipitate, which was filtered anddried to give 1-cyclopropyl-3-methylbutan-1-amine (1.5 g, 16%) as a paleyellow solid.

2-(Spiro[3.3]heptan-2-yl)propan-2-amine

Concentrated H₂SO₄ (0.5 mL) was added dropwise to a solution ofspiro[3.3]heptane-2-carboxylic acid (1 g, 7.14 mmol) in EtOH (30 mL) at0° C. and the reaction mixture was refluxed for 20 h. After completionof the reaction, the solvent was removed and the reaction mixture wasdissolved in EtOAc (150 mL). The organic layer was washed with saturatedNaHCO₃ solution (100 mL), dried over anhydrous MgSO₄, and filtered. Thefiltrate was concentrated in vacuo to give ethylspiro[3.3]heptane-2-carboxylate (1.2 g, 100%) as a colorless oil whichwas used directly in the next step. ¹H NMR (500 MHz, CDCl₃) δ 4.04 (q,J=7.0 Hz, 2H), 2.94-2.78 (m, 1H), 2.14 (p, J=11.0 Hz, 4H), 1.95 (t,J=7.5 Hz, 2H), 1.85 (t, J=7.4 Hz, 2H), 1.73 (dd, J=15.0 Hz, 7.5 Hz, 2H),1.17 (t, J=7.5 Hz, 3H).

To a solution of ethyl spiro[3.3]heptane-2-carboxylate (1.2 g, 7.14mmol) in anhydrous THF (20 mL) at −78° C. was added dropwise a solutionof MeMgBr (3.0 M in Et₂O; 9.52 mL, 28.56 mmol). The reaction mixture wasthen stirred at RT for 18 h, poured cautiously into sat. NH₄Cl solution(20 mL) and extracted with EtOAc (30 mL×3). The combine organic layerswere washed with brine (40 mL), dried over Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo to give2-(spiro[3.3]heptan-2-yl)propan-2-ol (1.0 g, 96%) as a colorless oil,which was used in the next step without further purification. ¹H NMR(500 MHz, DMSO-d₆) δ 3.94 (s, 1H), 2.02-2.04 (m, 1H), 1.96 (t, J=7.0 Hz,2H), 1.87-1.80 (m, 2H), 1.78-1.73 (m, 6H), 0.93 (s, 6H).

A stirred mixture of 2-(spiro[3.3]heptan-2-yl)propan-2-ol (1.0 g, 6.49mmol), TMSN₃ (2.95 g, 25.96 mmol) and molecular sieve (100 mg) in dryCH₂Cl₂ (40 mL) at RT under Ar was treated with BF₃.Et₂O (1.8 g, 12.98mmol). After stirring for 24 h, the resulting solution was quenched withwater (100 mL). The organic layer was separated, washed with saturatedNaHCO₃ solution (30 mL), water (30 mL) and brine (30 mL), dried overanhydrous MgSO₄ and filtered. The filtrate was concentrated in vacuo.The resulting residue was purified by silica gel column (PE/EtOAc; 3:1)to give 2-(2-azidopropan-2-yl)spiro[3.3]heptane (1.1 g) as a colorlessoil.

A mixture of 2-(2-azidopropan-2-yl)spiro[3.3]heptane (1.1 g, 6.14 mmol)and Pd/C (100 mg, 10% w/w) in MeOH (5 mL) was stirred under a H₂atmosphere at room temperature for 20 hours. The catalyst was removed byfiltration through a pad of celite and the filtrates were concentratedto give 2-(spiro[3.3]heptan-2-yl)propan-2-amine (580 mg, 52%) as acolorless oil. LC-MS m/z: 157.2 [M+H]⁺.

1-Cyclopropyl-2,2,2-trifluoroethan-1-amine

A suspension of cyclopropanecarbaldehyde (7.0 g, 100 mmol), benzylamine(11.2 g, 105 mmol) and MgSO₄ (62 g, 500 mmol) in DCM (200 mL) wasstirred for 48 h at RT. After reaction completion the solution wasfiltered through celite and the filtrate was concentrated in vacuo togive N-benzyl-1-cyclopropyl methanimine as a light yellow oil (16 g,100%). LC-MS weak MS: m/z: 159.1 [M+H]⁺.

To a solution of N-benzyl-1-cyclopropyl methanimine (6.0 g, 37.7 mmol)in MeCN (70 mL) was added KHF₂ (2.35 g, 30.2 mmol), CF₃COOH (5.54 g,48.6 mmol) and DMF (5 mL) and the mixture was stirred at RT. Thereaction mixture was cooled to 0° C. for 5 minutes, and then TMSCF₃ (8.4mL, 56.6 mmol) was added. After addition, the reaction mixture wasstirred for 12 h at RT until the starting material was completelyconsumed (LCMS). Saturated Na₂CO₃ solution (20 mL) was added, stirredfor 5 minutes and then 150 mL of water was added and the mixture wasextracted with EtOAc (150 mL×3). The organic phases were combined, driedover Na₂SO₄, filtered and concentrated in vacuo. The resulting residuewas purified by flash chromatography on silica gel (DCM:MeOH; 30:1 to5:1) to give N-benzyl-1-cyclopropyl-2,2,2-trifluoroethan-1-amine as acolorless oil (3.5 g, yield: 41%). LC-MS m/z: 230.1 [M+H]⁺. LC-MS Purity(214 nm): 97%; t_(R)=1.82 minutes.

To a solution of N-benzyl-1-cyclopropyl-2,2,2-trifluoroethan-1-amine(3.5 g, 15.3 mmol) in MeOH (50 mL) was added 6 N HCl (4 mL) at RT. Themixture was purged with N₂ three times and then Pd/C (350 mg, 10%, w/w)was added quickly under N₂ flow. The mixture was purged with H₂ threemore times, and stirred for 16 hours at room temperature. Pd/C wasremoved by filtration, and the filtrate was concentrated in vacuo togive 1-cyclopropyl-2,2,2-trifluoroethan-1-amine as a white solid (3.5 g,100%). ¹H NMR (500 MHz, DMSO-d₆) δ 9.35 (s, 3H), 3.63-3.58 (m, 1H),1.11-1.06 (m, 1H), 0.72-0.66 (m, 4H). LC-MS m/z: 140.2 [M+H]⁺.

1-(4,4-Difluorocyclohexyl)ethan-1-amine

To a solution of 4,4-difluorocyclohexane-1-carboxylic acid (1.64 g, 10mmol) and DIPEA (2.58 g, 20 mmol) in DMF (10 mL) at 0° C. was added HATU(5.7 g, 15 mmol) and the reaction mixture was stirred at 0° C. for 30min, followed by the addition of N, O-dimethylhydroxylaminehydrochloride (970 mg, 10 mmol). The reaction mixture was allowed towarm to RT and stirred overnight, then quenched with saturated NaHCO₃solution, and separated. The aqueous phase was extracted with EtOAc (100mL×3), and the combined organic phases were dried over Na₂SO₄, filteredand concentrated in vacuo. The resulting residue was purified by silicagel chromatography (PE/EtOAc; 4:1) to afford4,4-difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide (880 mg, 42%)as a colorless oil. LC-MS m/z: 208.0 [M+H]⁺. LCMS: t_(R)=1.58 min.

To a solution of4,4-difluoro-N-methoxy-N-methylcyclohexane-1-carboxamide (880 mg, 4.25mmol) in THF (12 mL) was added a solution of MeLi in 1,2-diethoxyethane(3 mol/L, 2 mL) dropwise at 0° C. After the addition was complete, thereaction mixture was allowed to warm to RT and stirred overnight, thenquenched with saturated NH₄Cl solution and separated. The aqueous phasewas extracted with EtOAc (120 mL×3), and the combined organic phaseswere dried over Na₂SO₄, filtered and concentrated in vacuo. Theresulting residue was purified by silica gel chromatography (PE/EA=4:1)to afford 1-(4,4-difluorocyclohexyl)ethan-1-one (400 mg, 43%) as a lightyellow oil. ¹H NMR (500 MHz, CDCl₃) δ 2.44 (m, 1H), 2.19 (s, 3H),2.13-2.16 (m, 2H), 1.96-1.98 (m, 2H), 1.74-1.83 (m, 4H).

A mixture of 1-(4,4-difluorocyclohexyl)ethan-1-one ((200 mg, 1.23 mmol),NH₄OAc (1.9 g, 24.6 mmol) and NaBH₃CN (388 mg, 6.15 mmol) in i-PrOH (15mL) was stirred at RT for 4 h and then at 90° C. for 2 h. Then, thereaction mixture was poured into water (15 mL), extracted with CH₂Cl₂(30 ml, ×3) and dried over Na₂SO₄, filtered and concentrated in vacuo.The resulting residue was purified by silica gel chromatography(EtOAc/MeOH; 10:1) to afford 1-(4,4-difluorocyclohexyl)ethan-1-amine asa colorless oil. LC-MS m/z: 164.1 [M+H]⁺. LCMS: t_(R)=1.13 min.

2-(4-Chlorophenyl)propan-2-amine

MgBrMe (3M in THF, 5 mL, 15 mmol) was added dropwise at RT to a solutionof 1-(4-chlorophenyl)ethan-1-one (1.54 g, 10 mol) in Et₂O (60 mL). Afterthe addition was complete the reaction mixture was stirred at RT for 12hours and then quenched by the careful addition of saturated NH₄Clsolution (30 mL). The resulting mixture was stirred for 1 hour and thenextracted with EtOAc (100 mL×3). The combined organic layers were driedover Na₂SO₄, filtered, concentrated in vacuo, and purified by silica gelchromatography (PE/EtOAc; 5:1) to give 2-(4-chlorophenyl)propan-2-ol(1.365 g, 80%) as a colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.42 (dd,J=6.8 Hz, 2.0 Hz, 2H), 7.29 (dd, J=6.8 Hz, 2.0 Hz, 2H), 1.78 (s, 1H),1.56 (s, 6H).

A mixture of 2-(4-chlorophenyl)propan-2-ol (1.36 g, 8 mmol), TMSN₃ (2.4g, 16 mmol) and BF₃.Et₂O (16 mL) in CH₂Cl₂ (20 mL) was stirred at RT for2 h and quenched with saturated NaHCO₃ solution. The resulting mixturewas separated, and the aqueous phase was extracted with CH₂Cl₂ (30mL×3). The combined organic phases were dried over Na₂SO₄ and filtered.The filtrate was concentrated in vacuo to afford the target compound1-(2-azidopropan-2-yl)-4-chlorobenzene as colorless oil, which was usedin the next step without further purification. LC-MS m/z: 153.0 [M-N₃]⁺.LCMS: Purity (254 nm): 44%; t_(R)=1.44 min.

The crude azide from the previous step was dissolved in THF (15 mL) atRT and trimethylphosphine (16 mL, 1.0 M in THF) was added. After 15minutes, 3 mL of water was added, and the resulting mixture was stirredat RT for 2 h until the reaction was complete (monitored by LC/MS.) Thesolvent was removed in vacuo and the resulting residue was diluted withwater (75 mL), extracted with CH₂Cl₂, dried over sodium sulfate andfiltered. The filtrate was concentrated in vacuo, and the resultingresidue was purified by reversed-phase chromatography (0.05% TFA/MeCN)to give the desired product 2-(4-chlorophenyl)propan-2-amine (200 mg,57% over two steps) as a pale oil. LC-MS m/z: 153.0 [M-NH₂]⁺. LCMS:Purity (214 nm): 98%; t_(R)=1.71 min.

(R)-1-Cyclopropyl-2,2,2-trifluoroethan-1-amine hydrochloride

To a mixture of 1-ethoxy-2,2,2-trifluoroethan-1-ol (10 g, 69.4 mmol) and(R)-2-methylpropane-2-sulfinamide (9.3 g, 76.7 mmol) was added Ti(OEt)₄(24 g, 105.3 mmol) and the mixture was stirred at 70° C. for 2 days,cooled, diluted with EA (200 mL) and poured into brine (700 mL). Theresulting mixture was stirred vigorously for several minutes andfiltered through celite. The cake was washed with EA, and the filtratewas extracted with EA (200 mL×3). The combined organic layers werewashed with brine (400 mL), dried over anhydrous Na₂SO₄, and filtered.The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (20-50% EA/PE) to afford stereoisomer A(8 g, 47%) and stereoisomer B (4 g, 23%) whose stereochemistry wasunassigned. Stereoisomer A (less polar): ¹H NMR (500 MHz, CDCl₃) δ4.75-4.70 (m, 1H), 4.09-4.03 (m, 1H), 3.9 (d, J=6.0 Hz, 1H), 3.68-3.62(m, 1H), 1.3-1.25 (m, 12H). LC-MS: m/z: no MS signal, t_(R)=1.655 min.Stereoisomer B (less polar): ¹H NMR (500 MHz, CDCl₃) δ 4.81-4.76 (m,1H), 4.3 (d, J=9.0 Hz, 1H), 3.94-3.88 (m, 1H), 3.66-3.60 (m, 1H),1.28-1.14 (m, 12H). m/z: no MS signal, t_(R)=1.614 min.

To a solution of stereoisomer A (5 g, 20.2 mmol) in 75 mL of DCM wasadded dropwise cPrMgBr in THF (1M, 61 mL, 61 mmol) at −60° C. and themixture was stirred for 10 minutes and then allowed to warm slowly to−20° C. over 2 h, during which time the reaction was complete. Thereaction mixture was quenched with saturated NH₄Cl solution (120 mL) andextracted with DCM (120 mL×3). The combined organic extracts were washedwith brine (160 mL), dried over anhydrous Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo, and the residue was purified bypreparative HPLC to afford(R)—N—((R)-1-cyclopropyl-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide(1.8 g, 37%). LC-MS m/z: 244.1 [M+H]⁺, t_(R)=1.74 min.

To a solution of(R)—N—((R)-1-cyclopropyl-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide(2.4 g, 9.9 mmol) in MeOH (5 mL) was added 4M HCl in dioxane (5 mL, 20mmol). The reaction mixture was stirred for 2 h at RT and concentratedin vacuo. The residue was triturated with Et₂O (10 mL×2) to afford thetitle compound (1.2 g, 71%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 9.46-9.26 (s, 3H), 3.63-3.56 (m, 1H), 1.12-1.05 (m, 1H), 0.73-0.58 (m,4H).

(S)-1-cyclopropyl-2,2,2-trifluoroethan-1-amine hydrochloride

To a mixture of 1-ethoxy-2,2,2-trifluoroethan-1-ol (20 g, 138.9 mmol)and (S)-2-methylpropane-2-sulfinamide (18.4 g, 152.8 mmol) was addedTi(OEt)₄ (48 g, 208.3 mmol). The mixture was stirred at 70° C. for 2 d,then cooled, diluted with EA (200 mL), and poured into brine (1.4 L) Theresulting mixture was stirred vigorously for several minutes andfiltered through celite. The cake was washed with EA, and the filtratewas extracted with EA (400 mL×3). The combined organic phases werewashed with brine (800 mL), dried over anhydrous Na₂SO₄, and filtered.The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (20-50% EA/PE) to afford stereoisomer C(11 g, 32%) and stereoisomer D (5.1 g, 15%) whose stereochemistry wasunassigned. Stereoisomer C (less polar): LC-MS m/z: no MS signal,t_(R)=1.669 min. Stereoisomer C (more polar): LC-MS m/z: no MS signal,t_(R)=1.626 min.

To a solution of stereoisomer C (9 g, 36.4 mmol) in 150 mL of DCM wasadded dropwise cPrMgBr in THF (1M, 109.3 mL, 109.3 mmol) at −60° C. andthe mixture was stirred for 10 minutes and allowed to warm slowly to−20° C. over 2 h, during which time the reaction was complete. Thereaction mixture was quenched with saturated NH₄Cl solution (80 mL) andextracted with DCM (120 mL×3). The combined organic extracts were washedwith brine (160 mL), dried over anhydrous Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo, and the residue was purified bypreparative HPLC to afford(S)—N—((S)-1-cyclopropyl-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide(3.5 g, 40%). LC-MS m/z: 244.1 [M+H]⁺, t_(R)=1.19 min.

To a solution of(S)—N—((S)-1-cyclopropyl-2,2,2-trifluoroethyl)-2-methylpropane-2-sulfinamide(1.16 g, 4.8 mmol) in MeOH (5 mL) was added 4M HCl in dioxane (5 mL, 20mmol). The reaction mixture was stirred for 30 min at RT andconcentrated to half volume. Et₂O was added to the mixture, and theresulting precipitate was filtered to afford the title compound (725 mg,40%) as a white solid. ¹H NMR: (500 MHz, DMSO-d₆) δ 9.30-9.00 (m, 3H),3.62-3.57 (m, 1H), 1.12-1.03 (m, 1H), 0.74-0.59 (m, 4H).

Part III—Preparation of Specific Carboxylic Acid Compounds

Exemplary procedures for preparing specific carboxylic acid compoundsuseful in the preparation of certain substitutedpyrazolo[1,5-a]pyrimidinyl carboxamide compounds are provided below.

7-Chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

To a solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (10 g, 64.5mmol) in HOAc (50 mL) was added 4-methyleneoxetan-2-one (27 g, 322.5mmol). The mixture was stirred at 110° C. for 2 h, then cooled andconcentrated in vacuo. The resulting residue was purified by silica gelcolumn chromatography (PE/EA; 10:3) to afford ethyl7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (8.0 g, 57%)and ethyl 5-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (3.1g, 21%) as white solids. 7-hydroxy product: LC-MS m/z: 221.0 [M+H]⁺,Purity (214 nm): >90%, t_(R)=1.26 min; 5-hydroxy product: LC-MS m/z:221.0 [M+H]⁺, Purity (214 nm): >92%, t_(R)=1.46 min.

A solution of ethyl7-hydroxy-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (4.4 g, 20mmol) in POCl₃ (30 mL) was stirred at 95° C. for 1 h and thenconcentrated in vacuo. The residue was dissolved in EtOAc (20 mL) andbasified with sat. NaHCO₃ solution (20 mL) to pH-7. The resultingmixture was separated, and the aqueous phase was extracted with EtOAc(15 mL×3). The combined organic phases were dried over anhydrous Na₂SO₄and filtered. The filtrate was concentrated in vacuo, and the residuewas purified by silica gel column chromatography (PE/EA; 1:1) to giveethyl 7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1.0 g,21%) as a white solid. LC-MS m/z: 239.0 [M+H]⁺, Purity (254 nm): >82%,t_(R)=1.55 min.

To a solution of ethyl7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1.0 g, 4.18mmol) in toluene (10 mL) was added (Bu₃Sn)₂O (5.0 g, 8.36 mmol). Thereaction mixture was stirred at 120° C. for 2 days, and thenconcentrated in vacuo. The resulting residue was dissolved in EtOAc (10mL), and basified with sat. NaHCO₃ solution (10 mL) to pH-8-9. Theaqueous phase was separated and acidified with 6N HCl (10 mL) to pH-5.The solution was extracted with EtOAc (10 mL×3). The organic phases weredried over anhydrous Na₂SO₄, and filtered. The filtrate was concentratedin vacuo, and the residue was purified by silica gel columnchromatography (PE/EA; 1:1) to give7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (230 mg,26%) as a white solid. LC-MS m/z: 211.0 [M+H]⁺, Purity (214 nm): >97%,t_(R)=1.23 min.

5-Chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A solution of ethyl5-hydroxy-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (2.8 g, 12.6mmol) in POCl₃ (30 mL) was stirred at 70° C. for 2 hr and thenconcentrated in vacuo. The resulting residue was dissolved in EtOAc (20mL) and basified with sat. NaHCO₃ solution (15 mL) to pH-7. Theresulting mixture was separated, and the aqueous phase was extractedwith EtOAc (10 mL×3). The combined organic phases were dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo,and the residue was purified by silica gel column chromatography (PE/EA;1:1) to give ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (2.7 g, 90%) asa white solid. LC-MS m/z: 239.0 [M+H]⁺, Purity (214 nm): >99%,t_(R)=1.74 min.

To a solution of ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1.0 g, 4.18mmol) in toluene (10 mL) was added (Bu₃Sn)₂O (5.0 g, 8.36 mmol). Thereaction mixture was stirred at 120° C. for 2 days, and thenconcentrated in vacuo. The resulting residue was dissolved in EtOAc (10mL), and basified with sat. NaHCO₃ solution (10 mL) to pH-8-9. Theaqueous phase was separated and acidified with 6N HCl (10 mL) to pH-5.The solution was extracted with EtOAc (10 mL×3). The organic phases weredried over anhydrous Na₂SO₄, and filtered. The filtrate was concentratedin vacuo, and the residue was purified by silica gel columnchromatography (PE/EA; 1:1) to give5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (330 mg,37%) as a white solid. LC-MS m/z: 211.0 [M+H]⁺, Purity (214 nm): >97%,t_(R)=1.28 min.

7-Methyl-5-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A solution of acetone (0.96 mL, 13.1 mmol) in carbon disulfide (1 g,13.1 mmol) was added to a suspension of sodium tert-butoxide (2.5 g,26.2 mmol) in THF (30 mL) while not allowing the temperature to exceed10° C. The reaction mixture was stirred at RT for 3 h and MeI (1.6 mL,26.2 mmol) was added at 10° C. and the resulting solution was stirredovernight at RT. The reaction mixture was diluted with EtOAc (100 mL),washed with water (30 mL×2) and the organic layer was dried over MgSO₄,and filtered. The filtrate was concentrated in vacuo and the crude waspurified by triturating with PE (30 mL) to give4,4-bis(methylthio)but-3-en-2-one (500 mg, 61%) as a yellow solid.

To a solution of 4,4-bis(methylthio)but-3-en-2-one (0.5 g, 3.08 mmol) ina mixture of acetic acid/water (3:1, 48 mL) was added ethyl3-amino-1H-pyrazole-4-carboxylate (0.36 g, 2.37 mmol) and a catalyticamount of piperidine (2 drops). The resulting solution was heated atreflux for 20 h then, after cooling, water was added (10 mL). Theprecipitated solid was collected by filtration and recrystallized from amixture of PE/ether (3:1) to furnish ethyl7-methyl-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carboxylate (500 mg,62%) as a yellow solid.

A suspension of m-CPBA (823 mg, 4.7 mmol) in DCM (5 mL) was added to astirred solution of ethyl7-methyl-5-(methylthio)pyrazolo[1,5-a]pyrimidine-3-carboxylate (400 mg,1.59 mmol) in DCM (5 mL). The resulting solution was stirred at RTovernight, the solvent was removed in vacuo and EtOH (15 mL) was addedto the residue. The solid was collected by filtration, washed with coldEtOH and dried to give ethyl7-methyl-5-(methylsulfonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (400mg, 89%) as a white solid.

A mixture of ethyl7-methyl-5-(methylsulfonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (400mg, 1.4 mmol) and MeNH₂ in MeOH (15 mL) was stirred at RT for 2 h. Thereaction mixture was diluted with water (30 mL) and extracted with EtOAc(3×25 mL). The organic layer was dried over Na₂SO₄, filtered andconcentrated in vacuo. The crude was purified by trituration with PE (10mL) to afford ethyl7-methyl-5-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (272 mg,61%) as a white solid.

The suspension of ethyl7-methyl-5-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (273 mg,1.15 mmol) in MeOH/H₂O (2 mL/2 mL) was treated with LiOH.H₂O (97 mg,2.31 mmol). The reaction mixture was heated to 60° C. and stirred for 5h. The reaction was cooled and neutralized to pH 6-7 with dilute HCl.The slurry was filtered, washed with water and diethyl ether to obtain7-methyl-5-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (154mg, 65%). LC-MS m/z: 207.0 [M+H]⁺: Purity (214 nm): >99%; t_(R)=0.46min.

Part IV—Pyrazolo[1,5-a]pyrimidine-3-carboxamide Compounds PreparedFollowing General Procedures

The following compounds were prepared based on the general proceduresdescribed in Part I above.

(S)—N-(1-Cyclopropylethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30 mg, 0.15mmol) and (S)-1-cyclopropylethan-1-amine afforded the title compound(19.0 mg, 49%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.48 (s,1H), 8.03 (d, J=7.5 Hz, 1H), 7.13 (s, 1H), 3.64-3.59 (m, 1H), 2.74 (s,3H), 2.63 (s, 3H), 1.25 (d, J=6.5 Hz, 3H), 1.04-0.99 (m, 1H), 0.51-0.41(m, 2H), 0.37-0.32 (m, 1H), 0.28-0.25 (m, 1H). LC-MS m/z: 259.2 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=9.31 min.

N-(2-Cyclopropylpropan-2-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.13mmol) and 2-cyclopropylpropan-2-amine afforded the title compound (8.0mg, 22%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 8.58 (s, 1H), 8.13(s, 1H), 6.68 (s, 1H), 2.78 (s, 3H), 2.62 (s, 3H), 1.44 (s, 6H),1.39-1.33 (m, 1H), 0.49 (d, J=6.5 Hz, 4H). LC-MS m/z: 272.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=9.99 min.

(R)—N-(1-Cyclohexylethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (38 mg, 0.20mmol) and (R)-1-cyclohexylethan-1-amine afforded the title compound as awhite solid (10 mg, 15%). ¹H NMR (500 MHz, DMSO-d₆): δ 8.47 (s, 1H),8.07 (d, J=8.5 Hz, 1H), 7.12 (s, 1H), 3.95-3.91 (m, 1H), 2.73 (s, 1H),2.61 (s, 1H), 1.82-1.62 (m, 5H), 1.47-1.41 (m, 1H), 1.27-1.03 (m, 2H),1.14 (d, J=6.5 Hz, 3H). LC-MS m/z: 301.3 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=10.81 min.

(S)—N-(1-Cyclohexylethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25 mg, 0.13mmol) and (S)-1-cyclohexylethan-1-amine afforded the title compound as ayellow solid (21.4 mg, 55%). ¹H NMR (500 MHz, CDCl₃): δ 8.61 (s, 1H),8.11 (d, J=8.5 Hz, 1H), 6.70 (s, 1H), 4.15-4.11 (m, 1H), 2.78 (s, 3H),2.64 (s, 3H), 1.89-1.87 (m, 1H), 1.79-1.77 (m, 4H), 1.69-1.66 (m, 1H),1.30-1.25 (m, 2H), 1.23 (d, J=6.5 Hz, 3H), 1.19-1.10 (m, 3H). LC-MS m/z:301.0 [M+H]⁺. HPLC: Purity (214 nm): >98%; t_(R)=10.82 min.

N-(1-Cyclopropyl-3-methylbutyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.21mmol) and 1-cyclopropyl-3-methylbutan-1-amine afforded the titlecompound (15 mg, 23%) as a pale yellow solid. ¹H NMR (500 MHz, CDCl₃) δ8.63 (s, 1H), 7.95 (d, J=9.0 Hz, 1H), 6.68 (s, 1H), 3.85-3.81 (m, 1H),2.79 (s, 3H), 2.65 (s, 3H), 1.84-1.78 (m, 1H), 1.64-1.52 (m, 2H), 0.96(d, J=6.5 Hz, 3H), 0.95 (d, J=6.5 Hz, 3H), 0.94-0.91 (m, 1H), 0.54-0.47(m, 2H), 0.46-0.40 (m, 1H), 0.33-0.28 (m, 1H). LC-MS m/z: 301.2 [M+H]⁺.HPLC: Purity (214 nm): >96%; t_(R)=10.70 min.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (41mg, 0.2 mmol) and (S)-1-cyclopropylethan-1-amine afforded the titlecompound (18 mg, 33%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.36 (s, 1H), 8.17 (s, 1H), 6.04 (s, 1H), 5.59 (s, 1H), 3.79-3.75 (m,1H), 3.08 (d, J=5.0 Hz, 3H), 2.64 (s, 3H), 1.34 (d, J=6.5 Hz, 3H),0.98-0.95 (m, 1H), 0.53-0.44 (m, 3H), 0.35-0.29 (m, 1H). LC-MS m/z:274.0 [M+H]⁺. HPLC Purity (254 nm): >96%; t_(R)=8.54 min.

(S)—N-(1-Cyclopropylethyl)-5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a suspension of 60% sodium hydride (36 g, 0.905 mol) in THF (700 mL)was added 1-(4-fluorophenyl)ethan-1-one (25.0 g, 0.184 mol) at 0° C.,and the mixture was stirred at RT for 30 min. To the mixture was addedEtOAc (63.7 g, 0.724 mol) at 0° C. The mixture was stirred at 40° C. for3 h, and then poured into 6 N HCl (20 mL). The organic solvent wasremoved in vacuo. The residual mixture was extracted with EtOAc (20mL×3), washed with 6 N HCl solution (15 mL) and brine (20 mL), driedover anhydrous MgSO₄, and filtered. The filtrate was concentrated invacuo to give 1-(4-fluorophenyl)butane-1,3-dione (20 g, 60%) as a brownoil LC-MS m/z: 180.0 [M+H]⁺, Purity (214 nm): >90%, t_(R)=1.88 min.

A solution of ethyl 3-amino-1H-pyrazole-4-carboxylate (6.0 g, 38.7 mmol)and 1-(4-fluorophenyl)butane-1,3-dione (7.62 g, 42.6 mmol) in aceticacid (10 0 mL) were heated at 110° C. overnight until the reaction wascomplete (LC-MS). Acetic acid was removed by blowing air with the flaskbeing heated to 75° C. The residue was triturated with MeOH (20 mL×2)and filtered to afford ethyl7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (2.88g, 29%) as a yellow solid. LC-MS m/z: 299.1 [M+H]⁺. LC-MS Purity (214nm): >96%; t_(R)=1.82 min.

The filtrate was concentrated in vacuo, and the residue was purified bysilica gel column, eluted with PE/EA (1:0 to 3:1) to afford ethyl5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (360mg, 4%) as a yellow solid (360 mg, 4%). LC-MS m/z: 299.1 [M+H]⁺. LC-MSPurity (214 nm): >66%; t_(R)=1.89 min.

Following general procedure B, ethyl5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (150mg, 0.5 mmol) afforded5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(140 mg, 99%). LC-MS m/z: 271.0 [M+H]⁺. LC-MS Purity (214 nm): >76%,t_(R)=1.59 min.

Following general procedure A,5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(43 mg, 0.16 mmol) and (S)-1-cyclopropylethan-1-amine afforded the titlecompound (38 mg, 71%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄) δ8.54 (s, 1H), 8.33-8.30 (m, 2H), 8.14 (d, J=7.5 Hz, 1H), 7.87 (s, 1H),7.48 (t, J=9.0 Hz, 2H), 3.63-3.59 (m, 1H), 2.84 (s, 3H), 1.30 (d, J=6.5Hz, 3H), 1.12-1.08 (m, 1H), 0.54-0.49 (m, 2H), 0.39-0.32 (m, 2H). LC-MSm/z: 339.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.66 min.

(S)—N-(1-Cyclopropylethyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure B, ethyl7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (750mg, 2.5 mmol) afforded7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(600 mg, 88%). LC-MS m/z: 271.0 [M+H]⁺. LC-MS Purity (214 nm): >99%,t_(R)=1.57 min.

Following general procedure A,7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(54 mg, 0.2 mmol) and S)-1-cyclopropylethan-1-amine afforded the titlecompound (19.8 mg, 29%) as a pale white solid. ¹H NMR (500 MHz, CDCl₃) δ8.64 (s, 1H), 8.16 (d, J=8.5 Hz, 1H), 8.05 (dd, J=8.5 Hz, 5.0 Hz, 2H),7.27 (t, J=8.5 Hz, 2H), 6.89 (s, 1H), 3.81-3.76 (m, 1H), 2.73 (s, 3H),1.37 (d, J=6.5 Hz, 3H), 1.02-1.00 (m, 1H), 0.55-0.45 (m, 3H), 0.34-0.31(m, 1H). LC-MS m/z: 339.0 [M+H]⁺. HPLC: Purity (254 nm): >99%;t_(R)=10.63 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40 mg, 0.21mmol) and 1-cyclopropyl-2,2,2-trifluoroethan-1-amine afforded the titlecompound (30.7 mg, 47%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.57 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 7.18 (s, 1H), 4.48-4.43 (m, 1H),2.76 (s, 3H), 2.63 (s, 3H), 1.27-1.23 (m, 1H), 0.69-0.64 (m, 1H),0.62-0.57 (m, 1H), 0.55-0.52 (m, 1H), 0.41-0.37 (m, 1H). LC-MS m/z:313.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.14 min.

N-([1,1′-bi(Cyclopropan)]-1-yl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (37 mg, 0.19mmol) and [1,1′-bi(cyclopropan)]-1-amine afforded the title compound(21.2 mg, 41%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.26 (s,1H), 8.05 (s, 1H), 6.89 (s, 1H), 2.51 (s, 3H), 2.29 (s, 3H), 1.24-1.19(m, 1H), 0.52-0.50 (m, 2H), 0.43-0.41 (m, 2H), 0.17-0.14 (m, 2H),0.01-0.00 (m, 2H). LC-MS m/z: 270.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=7.45 min.

5,7-Dimethyl-N-(2-(spiro[3.3]heptan-2-yl)propan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.26mmol) and 2-(spiro[3.3]heptan-2-yl)propan-2-amine afforded the titlecompound (18.4 mg, 22%) as a pale yellow solid. ¹H NMR (500 MHz,MeOD-d₄) δ 8.46 (s, 1H), 8.33 (s, 1H), 7.02 (s, 1H), 2.80 (s, 3H), 2.69(s, 3H), 2.61-2.57 (m, 1H), 2.14 (t, J=7.0 Hz, 2H), 2.08-1.86 (m, 8H),1.43 (s, 6H). LC-MS m/z: 327.2 [M+H]⁺. HPLC: Purity (214 nm): >95%;t_(R)=11.86 min.

7-Chloro-N-(2-cyclopropylpropan-2-yl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure C,7-chloro-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg,0.47 mmol) and 2-cyclopropylpropan-2-amine afforded the title compound(40 mg, 29%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.52 (s, 1H),7.96 (s, 1H), 7.57 (s, 1H), 2.63 (s, 3H), 1.34 (s, 7H), 0.45-0.44 (m,4H). LC-MS m/z: 292.7 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.25min.

5-Chloro-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure C,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg,0.47 mmol) and 2-cyclopropylpropan-2-amine afforded the title compound(60 mg, 43%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.55 (s, 1H),7.51 (s, 1H), 7.38 (s, 1H), 2.76 (s, 3H), 1.34-1.31 (m, 7H), 0.44-0.42(m, 4H). LC-MS m/z: 292.7 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.65min.

N—((R)-1-((1S,4S)-4-Methoxycyclohexyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamideandN—((R)-1-((1R,4R)-4-Methoxycyclohexyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.26mmol), HATU (100 mg, 0.26 mmol), and1-(4-methoxycyclohexyl)ethan-1-amine affordedN—((R)-1-((1S,4S)-4-methoxycyclohexyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide(7.2 mg) andN—((R)-1-((1R,4R)-4-methoxycyclohexyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide(8.4 mg).

N—((R)-1-((1S,4S)-4-Methoxycyclohexyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

¹H NMR (500 MHz, MeOD-d₄) δ 8.46 (s, 1H), 8.43 (s, 1H), 7.02 (s, 1H),3.37 (s, 3H), 3.22-3.17 (m, 1H), 2.80 (s, 3H), 2.67 (s, 3H), 2.20-2.18(m, 2H), 2.00-1.98 (m, 3H), 1.48 (s, 6H), 1.31-1.21 (m, 4H). LC-MS m/z:345.2 [M+H]⁺. HPLC: Purity (214 nm): 99.52%; t_(R)=8.08 min.

N—((R)-1-((1R,4R)-4-Methoxycyclohexyl)ethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ 8.46 (s, 1H), 8.44 (s, 1H), 7.02 (s, 1H),3.51-3.50 (m, 1H), 0.3.35 (s, 3H), 2.80 (s, 3H), 2.69 (s, 3H), 2.10-2.07(m, 2H), 1.99-1.96 (m, 1H), 1.87-1.66 (m, 2H), 1.54-1.48 (m, 6H), 1.48(s, 6H), 0.87 (d, J=7.0 Hz, 1H). LC-MS m/z: 345.2 [M+H]⁺. HPLC: Purity(214 nm): 95.63%; t_(R)=8.46 min.

N-(2-Cyclopropylpropan-2-yl)-7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideandN-(2-Cyclopropylpropan-2-yl)-5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of methyl picolinate (4.0 g, 29.20 mmol) in THF (60 mL)was added acetone (10 mL) at 0° C. After 5 minutes, MeONa/MeOH (28%, 20mL) was added dropwise and the mixture was stirred at RT for 2 h. Thesolvent was removed by concentration and the residue was acidified with10% HCl to pH 5˜6. The aqueous solution was extracted with EtOAc (100mL×3). The organic phase was dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo and the residue purified by silica gelchromatography (PE/EA=10:1) to give(Z)-4-hydroxy-4-(pyridin-2-yl)but-3-en-2-one (3.0 g, 84%).

To a mixture of (Z)-4-hydroxy-4-(pyridin-2-yl)but-3-en-2-one (1.43 g,9.20 mmol) in AcOH (20 mL) was added ethyl3-amino-1H-pyrazole-4-carboxylate (1.5 g, 9.20 mmol) and the mixture wasstirred at 110° C. for 2 h and then concentrated in vacuo. The residuewas triturated in a mixed solvent of petroleum ether and EtOAc (10:1, 30mL) and collected by filtration to give a mixture of ethyl5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate andethyl 7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(2.5 g, 87%) as a white solid. LC-MS m/z: 283.1 [M+H]⁺. t_(R)=1.74 min &1.86 min.

Following general procedure B, the mixture of ethyl5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate andethyl 7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(collectively 1.0 g, 3.54 mmol) afforded a mixture of5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(800 mg, 89%) as a white solid. LC-MS m/z: 255.1 [M+H]⁺. t_(R)=1.15 min& 1.20 min.

Following general procedure A, a mixture of5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(100 mg, 0.4 mmol) and 2-cyclopropylpropan-2-amine affordedN-(2-cyclopropylpropan-2-yl)-7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(8.1 mg, 25.6%) andN-(2-cyclopropylpropan-2-yl)-5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(26.1 mg, 25.6%) as pale white solids.

N-(2-Cyclopropylpropan-2-yl)-7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide:¹H NMR (500 MHz, DMSO-d₆) δ 8.81 (d, J=4.0 Hz, 1H), 8.57 (s, 1H), 8.48(d, J=8.0 Hz, 1H), 8.14 (d, J=7.0 Hz, 1H), 8.13 (s, 1H), 8.10 (dd, J=8.0Hz, 1.5 Hz, 1H), 7.62 (ddd, J=8.0 Hz, 5.0 Hz, 1.0 Hz, 1H), 2.89 (s, 3H),1.47-1.44 (m, 1H), 1.40 (s, 6H), 0.52-0.50 (m, 4H). LC-MS m/z: 336.1[M+H]⁺. HPLC: Purity (254 nm): 96.71%; t_(R)=10.58 min.

N-(2-Cyclopropylpropan-2-yl)-5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

¹H NMR (500 MHz, DMSO-d₆) δ 8.93 (d, J=8.0 Hz, 1H), 8.87 (d, J=3.5 Hz,1H), 8.55 (s, 1H), 8.17 (s, 1H), 8.12 (td, J=8.0 Hz, 1.5 Hz, 1H), 7.82(s, 1H), 7.68 (ddd, J=8.0 Hz, 5.0 Hz, 1.0 Hz, 1H), 2.74 (s, 3H), 1.38(s, 6H), 1.36-1.34 (m, 1H), 0.48 (d, J=7.5 Hz, 4H). LC-MS m/z: 336.1[M+H]⁺. HPLC: Purity (254 nm): 98.73%; t_(R)=10.77 min.

N-(2-Cyclopropylpropan-2-yl)-7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (500 mg, 2.1mmol) and pyridin-3-ylboronic acid afforded ethyl7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (425mg, 71%) as a yellow solid. LC-MS m/z: 283.1 [M+H]⁺. Purity (214nm): >90%; t_(R)=1.51 min.

Following general procedure B, ethyl7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (425mg, 1.5 mmol) afforded7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(362 mg, 95%). LC-MS m/z: 255.0 [M+H]⁺, Purity (254 nm): >95%;t_(R)=1.24 min.

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (36mg, 0.14 mmol) and 2-cyclopropylpropan-2-amine afforded the titlecompound (15 mg, 32%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.43(s, 1H), 8.75 (d, J=4.8 Hz, 1H), 8.56 (d, J=9.6 Hz, 1H), 8.54 (s, 1H),8.13 (s, 1H), 7.94 (s, 1 H), 7.64 (dd, J=8.0 Hz, 4.0 Hz, 1H), 2.84 (s,3H), 1.39-1.36 (m, 1H), 1.36 (s, 6H), 0.48-0.46 (m, 4H). LC-MS m/z:336.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.37 min.

N-(2-Cyclopropylpropan-2-yl)-7-methyl-5-(pyridin-4-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 0.84mmol) and pyridin-4-ylboronic afforded ethyl7-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (170mg, 72%) as a white solid. LC-MS m/z: 283.1 [M+H]⁺.

Following general procedure B, ethyl7-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (170mg, 0.6 mmol) afforded7-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(140 mg, 92%) as a white solid. LC-MS m/z: 255.1 [M+H]⁺.

Following general procedure A,7-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40mg, 0.16 mmol) and 2-cyclopropylpropan-2-amine afforded the titlecompound (17 mg, 31%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.85 (d, J=6.0 Hz, 2H), 8.60 (s, 1H), 8.17 (d, J=5.5 Hz, 2H), 8.11 (s,1H), 8.00 (s, 1H), 2.88 (s, 3H), 1.45-1.40 (m, 1H), 1.39 (s, 6H),0.50-0.49 (m, 4H). LC-MS m/z: 336.1 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=7.23 min.

N-(2-Cyclopropylpropan-2-yl)-7-methyl-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (118 mg, 0.49mmol) and piperidine afforded ethyl7-methyl-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (120mg, 85%) as a yellow solid. LC-MS m/z: 289.1 [M+H]⁺.

Following general procedure B, ethyl7-methyl-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (120mg, 0.4 mmol) afforded7-methyl-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(98 mg, 92%) as a white solid. LC-MS m/z: 261.2 [M+H]⁺.

Following general procedure A,7-methyl-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(35 mg, 0.13 mmol) and 2-cyclopropylpropan-2-amine afforded the titlecompound (12 mg, 27%). ¹H NMR (500 MHz, DMSO-d₆): δ 8.10 (s, 1H), 7.88(s, 1H), 6.84 (s, 1H), 3.72 (t, J=5.0 Hz, 4H), 2.59 (s, 3H), 1.70-1.66(m, 2H), 1.60-1.58 (m, 4H), 1.30 (s, 6H), 1.29-1.27 (m, 1H), 0.39-0.36(m, 4H). LC-MS m/z: 342.3 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.73min.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamideand(S)—N-(1-Cyclopropylethyl)-5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A, a mixture of5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(100 mg, 0.39 mmol) and (S)-1-cyclopropylethan-1-amine afforded(S)—N-(1-cyclopropylethyl)-7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(21.6 mg, 17%) and(S)—N-(1-cyclopropylethyl)-5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(57.5 mg, 46%) as white solids.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

¹H NMR (400 MHz, MeOD-d₄) δ 8.77 (d, J=5.2 Hz, 1H), 8.60 (s, 1H), 8.51(d, J=7.6 Hz, 1H), 8.15 (s, 1H), 8.05 (td, J=8.0 Hz, 1.6 Hz, 1H), 7.57(ddd, J=7.6 Hz, 4.8 Hz, 0.8 Hz, 1H), 3.72-3.65 (m, 1H), 2.93 (s, 3H),1.41 (d, J=6.8 Hz, 3H), 1.21-1.12 (m, 1H), 0.68-0.55 (m, 2H), 0.52-0.46(m, 1H), 0.43-0.37 (m, 1H). LC-MS m/z: 322.1 [M+H]⁺. HPLC: Purity (214nm): 95.44%; t_(R)=7.95 min.

(S)—N-(1-Cyclopropylethyl)-5-methyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

¹H NMR (400 MHz, DMSO-d₆) δ 8.92 (d, J=8.0 Hz, 1H), 8.87 (d, J=4.8 Hz,1H), 8.60 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.11 (dd, J=8.0 Hz, 2.0 Hz,1H), 7.68 (ddd, J=7.6 Hz, 4.8 Hz, 0.8 Hz, 1H), 3.67-3.59 (m, 1H), 2.76(s, 3H), 1.27 (d, J=6.0 Hz, 3H), 1.08-1.01 (m, 1H), 0.53-0.42 (m, 2H),0.39-0.34 (m, 1H), 0.31-0.25 (m, 1H). LC-MS m/z: 322.2 [M+H]⁺. HPLC:Purity (254 nm): 98.89%; t_(R)=8.09 min.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (36mg, 0.14 mmol) and (S)-1-cyclopropylethanamine afforded the titlecompound (18 mg, 40%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.43(s, 1H), 8.76 (d, J=4.0 Hz, 1H), 8.59-8.58 (m, 2H), 8.11 (d, J=6.7 Hz,1H), 7.96 (s, 1H), 7.66 (dd, J=8.0 Hz, 4.8 Hz, 1H), 3.60 (m, J=6.8 Hz,1H), 2.85 (s, 3H), 1.28 (d, J=6.4 Hz, 3H), 1.11-1.07 (m, 1H), 0.52-0.29(m, 4H). LC-MS m/z: 322.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=6.78min.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40mg, 0.16 mmol) and (S)-1-cyclopropylethanamine afforded the titlecompound (6.7 mg, 13%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.86 (dd, J=4.5 Hz, 1.5 Hz, 2H), 8.64 (s, 1H), 8.19 (dd, J=4.5 Hz, 1.5Hz, 2H), 8.12 (d, J=4.0 Hz, 1H), 8.02 (s, 1H), 3.64-3.59 (m, 1H), 2.88(s, 3H), 1.30 (d, J=6.5 Hz, 3H), 1.15-1.12 (m, 1H), 0.54-0.48 (m, 2H),0.40-0.33 (m, 2H). LC-MS m/z: 322.1 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=6.67 min.

(S)—N-(1-Cyclopropylethyl)-5-methyl-7-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.19mmol) and (S)-1-cyclopropylethanamine afforded the title compound (13mg, 21%) as a pale white solid. ¹H NMR (500 MHz, MeOD-d₄) δ 8.38 (s,1H), 6.40 (s, 1H), 3.83-3.82 (m, 4H), 3.72-3.68 (m, 1H), 2.58 (s, 3H),1.82-1.78 (m, 6H), 1.36 (d, J=7.0 Hz, 3H), 1.05-1.03 (m, 1H), 0.58-0.52(m, 2H), 0.44-0.42 (m, 1H), 0.32-0.30 (m, 1H). LC-MS m/z: 328.3 [M+H]⁺.HPLC: Purity (254 nm): >99%; t_(R)=10.18 min.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(piperidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(35 mg, 0.13 mmol) and (S)-1-cyclopropylethanamine afforded the titlecompound (17 mg, 39%). ¹H NMR (500 MHz, DMSO-d₆): δ 8.13 (s, 1H), 7.96(d, J=5.0 Hz, 1H), 6.86 (s, 1H), 3.73 (t, J=5.0 Hz, 4H), 3.57-5.36 (m,1H), 2.60 (s, 3H), 1.70-1.67 (m, 2H), 1.61-1.58 (m, 4H), 1.19 (d, J=6.5Hz, 3H), 0.95-0.94 (m, 1H), 0.46-0.39 (m, 2H) 0.30-0.23 (m, 2H). LC-MSm/z: 328.3 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.18 min.

(S)-2-Chloro-N-(1-cyclopropylethyl)-5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution of ethyl5-amino-3-chloro-1H-pyrazole-4-carboxylate (200 mg, 1.05 mmol) in HOAc(5 mL) was added 1-(4-fluorophenyl)butane-1,3-dione (380 mg, 2.11 mmol)at 110° C. The solution was stirred for approximately 4 h at thistemperature, cooled and concentrated in vacuo. The resulting residue wasdissolved in MeOH (2 mL) and purified by reverse-phase chromatography(MeCN\% TFA) to afford ethyl2-chloro-5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(80 mg, 22%) and ethyl2-chloro-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(200 mg, 57%) as white solids. 7-Me Product: LC-MS: m/z: 333.0 [M+H]⁺;Purity (214 nm): >92%; t_(R)=1.99 min. 5-Me Product: LC-MS: m/z: 333.0[M+H]⁺; Purity (214 nm): >99%; t_(R)=1.91 min.

Following general procedure B, ethyl2-chloro-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(80 mg, 0.24 mmol) afforded2-chloro-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (60 mg, 82%) as a white solid. LC-MS: m/z: 305.0 [M+H]⁺; Purity(214 nm): >92%; t_(R)=1.69 min.

Following general procedure A,2-chloro-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.1 mmol) and (S)-1-cyclopropylethanamine afforded thetitle compound (15.6 mg, 43%) as white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.34-8.30 (m, 3H), 7.97 (s, 1H), 7.49 (t, J=8.5 Hz, 2H), 3.61-3.33 (m,1H), 2.80 (s, 3H), 1.28 (d, J=6.5 Hz, 3H), 1.12-1.07 (m, 1H), 0.54-0.47(m, 2H), 0.39-0.31 (m, 2H). LC-MS m/z: 372.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=9.21 min.

(S)-2-Chloro-N-(1-cyclopropylethyl)-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure B, ethyl2-chloro-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(75 mg, 0.23 mmol) afforded2-chloro-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (47 mg, 69%) as a white solid. LC-MS: m/z: 305.0 [M+H]⁺; Purity(214 nm): >92%; t_(R)=1.67 min.

Following general procedure A,2-chloro-7-(4-fluorophenyl)-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (37 mg, 0.12 mmol) and (S)-1-cyclopropylethanamine afforded thetitle compound (26 mg, 59%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.31 (d, J=8.0 Hz, 1H), 8.15-8.12 (m, 2H), 7.52-7.49 (m, 2H), 7.48 (s,1H), 3.66-3.59 (m, 1H), 2.70 (s, 3H), 1.26 (d, J=7.0 Hz, 3H), 1.05-1.07(m, 1H), 0.50-0.44 (m, 2H), 0.38-0.25 (m, 2H). LC-MS m/z: 372.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=9.19 min.

(S)-2-Chloro-N-(1-cyclopropylethyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of ethyl 5-amino-3-chloro-1H-pyrazole-4-carboxylate (80 mg,0.84 mmol) and pentane-2,4-dione (84 mg, 0.84 mmol) in AcOH (1 ml) wasstirred at 100° C. for 2 h until the reaction was complete (LC-MS). Theacetic acid was removed in vacuo and the residue was purified by silicagel column chromatography (PE/EA: 2/1) to give ethyl2-chloro-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg,94%) as a white solid. LC-MS m/z: 253.9 [M+H]⁺. LC-MS: Purity (214 nm):95%; t_(R)=1.66 min.

Following general procedure B, ethyl2-chloro-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg,0.4 mmol) afforded2-chloro-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid as awhite solid (70 mg, 78.7%). LC-MS m/z: 226.1 [M+H]⁺. LCMS: Purity (214nm): 93.51%; t_(R)=0.65 min.

Following general procedure A,2-chloro-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (30 mg,0.13 mmol) and (S)-1-cyclopropylethanamine afforded the title compound(22.6 mg, 57.9%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.24 (d,J=7.0 Hz, 1H), 6.74 (s, 1H), 3.78-3.74 (m, 1H), 2.76 (s, 3H), 2.65 (s,3H), 1.34 (d, J=6.5 Hz, 3H), 1.00-0.97 (m, 1H), 0.54-0.44 (m, 3H),0.32-0.29 (m, 1H). LC-MS m/z: 293.1 [M+H]⁺. LCMS: Purity (214 nm): >99%;t_(R)=1.88 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40mg, 0.16 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine afforded thetitle compound (14 mg, 23%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄)δ 9.42 (d, J=1.5 Hz, 1H), 8.77 (dd, J=5.0 Hz, 1.5 Hz, 1H), 8.67 (s, 1H),8.65 (tt, J=8.5 Hz, 2.0 Hz, 1H), 7.84 (s, 1H), 7.70 (ddd, J=8.0 Hz, 5.0Hz, 0.5 Hz, 1H), 4.48-4.41 (m, 1H), 2.98 (s, 3H), 1.37-1.30 (m, 1H),0.82-0.77 (m, 1H), 0.70-0.65 (m, 1H), 0.63-0.58 (m, 1H), 0.54-0.49 (m,1H). LC-MS m/z: 376.2 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=9.23min

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50mg, 0.20 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine afforded thetitle compound (36 mg, 48%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄)δ 8.80 (d, J=4.0 Hz, 1H), 8.66 (s, 1H), 8.48 (d, J=7.5 Hz, 1H), 8.21 (s,1H), 8.06 (td, J=7.5 Hz, 1.5 Hz, 1H), 7.59 (ddd, J=7.5 Hz, 5.0 Hz, 1.0Hz, 1H), 4.49-4.42 (m, 1H), 2.97 (s, 3H), 1.41-1.34 (m, 1H), 0.83-0.78(m, 1H), 0.71-0.66 (m, 1H), 0.64-0.59 (m, 1H), 0.57-0.52 (m, 1H). LC-MSm/z: 376.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=10.51 min.

(R)—N-(1-(4-Chlorophenyl)ethyl)-7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25mg, 0.18 mmol) and (R)-1-(4-chlorophenyl)ethanamine afforded the titlecompound (8.7 mg, 22%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄): δ9.37 (dd, J=2.5 Hz, 1.0 Hz, 1H), 8.75 (dd, J=10.0 Hz, 2.0 Hz, 1H), 8.62(s, 1H), 8.51 (ddd, J=8.0 Hz, 2.5 Hz, 1.5 Hz, 1H), 7.79 (d, J=1.0 Hz,1H), 7.65 (ddd, J=8.0 Hz, 5.0 Hz, 1.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 2H),7.41 (d, J=8.0 Hz, 2H), 5.28 (q, J=6.5 Hz, 1H), 2.95 (d, J=0.5 Hz, 3H),1.69 (d, J=7.0 Hz, 3H). LC-MS m/z: 392.0 [M+H]⁺. HPLC Purity (214 nm):99%; t_(R)=7.80 min.

N-((1R,4R)-4-tert-Butoxycyclohexyl)-7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40mg, 0.15 mmol) and (1R,4R)-4-tert-butoxycyclohexanamine afforded thetitle compound (20 mg, 33%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃) δ9.38 (d, J=2.0 Hz, 1H), 8.82 (dd, J=4.5 Hz, 2.0 Hz, 1H), 8.73 (s, 1H),8.34 (tt, J=7.5 Hz, 2.0 Hz, 1H), 7.95 (d, J=8.0 Hz, 1H), 7.56 (dd, J=7.5Hz, 4.5 Hz, 1H), 7.30 (s, 1H), 4.04-3.98 (m, 1H), 3.50-3.46 (m, 1H),2.96 (s, 3H), 2.24-2.21 (d, 2H), 1.92-1.90 (m, 2H), 1.56-1.53 (m, 2H),1.44-1.40 (m, 2H), 1.24 (s, 9H). LC-MS m/z: 408.3 [M+H]⁺. HPLC: Purity(254 nm): >99%; t_(R)=7.44 min.

N-((1R,4R)-4-Isobutoxycyclohexyl)-7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40mg, 0.15 mmol) and (1R,4R)-4-isobutoxycyclohexanamine afforded the titlecompound (16 mg, 26%) as a yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 9.36(t, J=1.0 Hz, 1H), 8.82 (dd, J=4.5 Hz, 1.0 Hz, 1H), 8.74 (s, 1H), 8.35(tt, J=7.5 Hz, 2.0 Hz, 1H), 8.03 (d, J=7.0 Hz, 1H), 7.55 (ddd, J=8.0 Hz,5.0 Hz, 0.5 Hz, 1H), 7.31 (d, J=1.0 Hz, 1H), 4.12-4.06 (m, 1H),3.38-3.28 (m, 1H), 3.25 (d, J=6.0 Hz, 2H), 2.96 (d, J=0.5 Hz, 3H),2.26-2.23 (d, 2H), 2.12-2.08 (m, 2H), 1.54-1.50 (m, 2H), 1.44-1.40 (m,2H), 0.94 (d, J=6.5 Hz, 6H). LC-MS m/z: 408.3 [M+H]⁺. HPLC: Purity (254nm): >99%; t_(R)=8.07 min.

7-Methyl-N-((1R,4R)-4-propoxycyclohexyl)-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (25mg, 0.18 mmol) and (1R,4R)-4-propoxycyclohexanamine afforded the titlecompound (9 mg, 22%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄): δ9.42 (dd, J=2.5 Hz, 1.0 Hz, 1H), 8.77 (dd, J=5.0 Hz, 1.5 Hz, 1H), 8.65(ddd, J=7.5 Hz, 2.0 Hz, 1.5 Hz, 1H), 8.63 (s, 1H), 7.80 (d, J=0.5 Hz,1H), 7.70 (ddd, J=7.5 Hz, 5.0 Hz, 1.0 Hz, 1H), 4.01-3.97 (m, 1H), 3.51(t, J=6.5 Hz, 2H), 3.45-3.41 (m, 1H), 2.95 (d, J=0.5 Hz, 3H), 2.22-2.13(m, 4H), 1.65-1.59 (m, 2H), 1.57-1.47 (m, 4H), 0.97 (t, J=7.5 Hz, 3H).LC-MS m/z: 394.2 [M+H]⁺. HPLC Purity (214 nm): 99%; t_(R)=7.35 min

7-Methyl-5-(pyridin-3-yl)-N-(1,1,1-trifluoro-3-methylbutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40mg, 0.16 mmol) and 1,1,1-trifluoro-3-methylbutan-2-amine afforded thetitle compound (8 mg, 13%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄) δ9.40 (dd, J=2.5 Hz, 0.5 Hz, 1H), 8.76 (dd, J=5.0 Hz, 2.0 Hz, 1H), 8.69(s, 1H), 8.63 (ddd, J=8.0 Hz, 2.5 Hz, 2.0 Hz, 1H), 7.84 (d, J=1.0 Hz,1H), 7.68 (ddd, J=8.0 Hz, 5.0 Hz, 1.0 Hz, 1H), 4.92-4.85 (m, 1H), 2.98(d, J=0.5 Hz, 3H), 2.424-2.37 (m, 1H), 1.17 (d, J=6.5 Hz, 3H), 1.09 (d,J=6.5 Hz, 3H). LC-MS m/z: 377.9 [M+H]⁺. HPLC: Purity (254 nm): >99%;t_(R)=7.79 min.

7-Methyl-5-(pyridin-3-yl)-N-(1,1,1-trifluorobutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50mg, 0.20 mmol) and 1,1,1-trifluorobutan-2-amine afforded the titlecompound (20 mg, 28%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄) δ 9.40(dd, J=2.0 Hz, 1H), 8.76 (dd, J=5.0 Hz, 1.5 Hz, 1H), 8.68 (s, 1H), 8.64(ddd, J=8.0 Hz, 2.0 Hz, 1.5 Hz, 1H), 7.84 (d, J=1.5 Hz, 1H), 7.69 (ddd,J=8.0 Hz, 5.0 Hz, 0.5 Hz, 1H), 4.87-4.80 (m, 1H), 2.98 (s, 3H),2.12-2.04 (m, 1H), 1.86-1.76 (m, 1H), 1.12 (t, J=7.5 Hz, 3H). LC-MS m/z:364.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=9.11 min.

7-Methyl-5-(pyridin-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (40mg, 0.16 mmol) and 1,1,1-trifluoropropan-2-amine afforded the titlecompound (14 mg, 26%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄) δ 9.41(d, J=2.0 Hz, 1H), 8.77 (dd, J=5.0 Hz, 1.5 Hz, 1H), 8.68 (s, 1H), 8.65(tt, J=8.5 Hz, 2.0 Hz, 1H), 7.84 (s, 1H), 7.70 (dd, J=8.0 Hz, 5.0 Hz,1H), 5.03-4.97 (m, 1H), 2.97 (s, 3H), 1.55 (d, J=7.5 Hz, 3H). LC-MS m/z:350.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=8.73 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (98 mg, 0.41mmol) in 5 mL of cyclopropanamine was stirred at 50° C. for 2 hr, thencooled and concentrated in vacuo. The resulting residue was purified byprep-TLC (PE/EA=1/1) to afford ethyl5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (90mg, 84%) as a yellow solid. LC-MS m/z: 261.1 [M+H]⁺.

Following general procedure B, ethyl5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (90mg, 0.35 mmol) afforded5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(40 mg, 49%) as a white solid. LC-MS m/z: 233.0 [M+H]⁺.

Following general procedure A,5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.13 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine affordedthe title compound (27 mg, 45%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.66 (s, 1H), 8.26 (s, 1H), 8.18 (s, 1H), 6.22 (s, 1H),4.41-4.36 (m, 1H), 2.72-2.66 (m, 1H), 2.56 (s, 3H), 1.19-1.11 (m, 1H),0.78 (d, J=6.0 Hz, 2H), 0.67-0.61 (m, 1H), 0.58-0.46 (m, 4H), 0.39-0.32(m, 1H). LC-MS m/z: 354.1 [M+H]⁺. HPLC Purity (214 nm): 92%; t_(R)=7.07min.

5-Chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg,0.23 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine afforded thetitle compound (15.7 mg, 20%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.71 (s, 1H), 8.07 (d, J=9.6 Hz, 1H), 7.44 (s, 1H), 4.42-4.32(m, 1H), 2.78 (s, 3H), 1.26-1.20 (m, 1H), 0.69-0.65 (m, 1H), 0.60-0.54(m, 2H), 0.38-0.33 (m, 1H). LC-MS m/z: 333.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.41 min.

(S)—N-(1-Cyclopropylethyl)-5-(4-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of ethyl5-hydroxy-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1.2g, 4.8 mmol) in 15 mL of PhPOCl₂ was stirred at 80° C. for 4 h under N₂,cooled to RT, and poured into 250 mL of ice-water. The resulting mixturewas basified to pH 8, and extracted with EA (200 mL×3). The organicphases were dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo, and the residue was purified by pre-TLC plate toafford ethyl5-chloro-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (40mg, 3%). LC-MS m/z: 270.3 [M+H]⁺.

Following general procedure D, ethyl7-chloro-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (150mg, 0.56 mmol) and 4-fluorophenyl boronic acid afforded ethyl5-(4-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(168 mg, 75%) as a yellow solid. LC-MS m/z: 330.1 [M+H]⁺. t_(R)=1.56min.

Following general procedure B, ethyl5-(4-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(80 mg, 0.24 mmol) at 30° C. afforded5-(4-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid sodium salt (72 mg, 99%) as an orange solid. LC-MS m/z: 302.0[M+H]⁺. t_(R)=1.76 min.

Following general procedure A,7-(4-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (35 mg, 0.12 mmol) and (S)-1-cyclopropylethanamine afforded thetitle compound (16.4 mg, 34%) as a pale yellow solid. 1H NMR (500 MHz,DMSO-d₆) δ 8.58 (s, 1H), 8.36 (dd, J=9.0 Hz, 5.5 Hz, 2H), 8.14 (d, J=7.5Hz, 1H), 7.76 (s, 1H), 7.49 (t, J=9.0 Hz, 2H), 5.04 (s, 2H), 3.62-3.59(m, 1H), 3.56 (s, 3H), 1.29 (d, J=6.5 Hz, 3H), 1.11-1.10 (m, 1H),0.54-0.48 (m, 2H), 0.38-0.32 (m, 2H). LC-MS m/z: 369.1 [M+H]⁺. HPLC:Purity (254 nm): 96%; t_(R)=9.74 min.

(S)—N-(1-Cyclopropylethyl)-7-(4-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of methyl 4-methoxy-3-oxobutanoate (15.0 g, 100 mmol) inEtOH (20 mL) was added conc. H₂SO₄ (1 drop, cat.) at RT under a N₂atmosphere. The mixture was heated to 80° C., followed by the additionof CH(OEt)₃ (15.2 g, 100 mmol) dropwise, stirred at 80° C. for 1 h, andconcentrated in vacuo to afford methyl 3-ethoxy-4-methoxybut-2-enoate(21 g, crude) as yellow oil. LC-MS m/z: 175.1 [M+H]⁺. LCMS: t_(R)=1.72min.

To a solution of methyl 3-ethoxy-4-methoxybut-2-enoate (3.5 g, 18.60mmol) in DMF (15 mL) was added ethyl 5-amino-1H-pyrazole-4-carboxylate(3.0 g, 19.40 mmol) and Cs₂CO₃ (7.3 g, 22.30 mmol). The mixture wasstirred at 110° C. for 4 h, and filtrated. The filtrate was purified byprep-HPLC (10 mM NH₄HCO₃, CH₃CN:H₂O=5%-95%) to afford give ethyl7-hydroxy-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (3.3g, 68%) and ethyl5-hydroxy-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.83g, 17%) as yellow solids.

Ethyl7-hydroxy-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate:LC-MS m/z: 252.1 [M+H]⁺. LCMS: t_(R)=1.45 min.

Ethyl5-hydroxy-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate:LC-MS m/z: 252.1 [M+H]⁺. LCMS: t_(R)=1.37 min.

The mixture of ethyl7-hydroxy-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (200mg, 0.80 mmol) in phenylphosphonic dichloride (2.5 mL) was stirred at110° C. for 3 hours, poured into ice and extracted with EA (50 mL×3).The organic phases were washed with NaHCO₃ aqueous solution (100 mL),dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentratedin vacuo to afford ethyl7-chloro-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (200mg, 94%) as a brown solid. LC-MS m/z: 270.1 [M+H]⁺. LCMS: t_(R)=1.75min.

Following general procedure D, ethyl7-chloro-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (200mg, 0.74 mmol) and 4-fluorophenyl boronic acid afforded ethyl7-(4-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(80 mg, 33%) as a yellow solid. LC-MS m/z: 330.1 [M+H]⁺. t_(R)=1.58 min.

Following general procedure B, ethyl7-(4-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(80 mg, 0.24 mmol) afforded7-(4-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid sodium salt (72 mg, 98%) as a yellow solid. LC-MS m/z: 302.1[M+H]⁺. LCMS: t_(R)=1.64 min.

Following general procedure A,7-(4-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (24 mg, 0.08 mmol) and (S)-1-cyclopropylethanamine afforded thetitle compound as a yellow solid (10.3 mg, 35%). ¹H NMR (500 MHz,MeOD-d₄) δ 8.57 (s, 1H), 8.38 (dd, J=8.5 Hz, 5.5 Hz, 2H), 8.13 (d, J=8.0Hz, 1H), 7.75 (s, 1H), 7.48 (t, J=8.5 Hz, 2H), 5.04 (s, 2H), 3.62-3.59(m, 1H), 3.56 (s, 3H), 1.29 (d, J=6.5 Hz, 3H), 1.11-1.10 (m, 1H),0.54-0.48 (m, 2H), 0.38-0.32 (m, 2H). LC-MS m/z: 369.1 [M+H]⁺. HPLC:Purity (254 nm): 99%; t_(R)=9.61 min.

N-(2-Cyclopropylpropan-2-yl)-5-(4-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(4-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (36 mg, 0.12 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (9 mg, 20%) as a yellow solid. 1H NMR (500 MHz, MeOD-d₄):δ 8.52 (s, 1H), 8.46 (brs, 1H), 8.30 (dd, J=9.0 Hz, 5.5 Hz, 1H), 7.71(s, 1H), 7.33 (t, J=9.0 Hz, 1H), 5.05 (s, 2H), 3.67 (s, 3H) 1.48 (s,6H), 1.48-1.42 (m, 1H), 0.60-0.56 (m, 4H). LC-MS m/z: 383.2 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=10.29 min.

N-(2-Cyclopropylpropan-2-yl)-7-(4-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-(4-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (24 mg, 0.08 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (12.7 mg, 42%) as a white solid. 1H NMR (500 MHz,MeOD-d₄) δ 8.52 (s, 1H), 8.46 (s, 1H), 8.30 (dd, J=8.5 Hz, 5.5 Hz, 2H),7.72 (s, 1H), 7.35 (t, J=8.5 Hz, 2H), 5.06 (s, 2H), 3.68 (s, 3H), 1.48(s, 6H), 1.46-1.41 (m, 1H), 0.59-0.56 (m, 4H). LC-MS m/z: 383.1 [M+H]⁺.HPLC: Purity (254 nm): 97%; t_(R)=10.13 min.

(S)—N-(1-Cyclopropylethyl)-5-ethyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Into the stirred solution of methyl 3-ethoxypent-2-enoate (10.0 g, 63.3mmol) and ethyl 5-amino-1H-pyrazole-4-carboxylate (9.8 g, 63.3 mmol) inDMF (200 mL) was added Cs₂CO₃ (61.7 g, 189.9 mmol). The mixture wasstirred at 100° C. for 24 h, and concentrated in vacuo. The residue wastreated with MeOH (400 mL). The solid was filtered off, and the filtratewas concentrated in vacuo. The residues was purified by prep-TLC(PE:EA=1:1) to afford ethyl5-ethyl-7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (0.8 g, 5.7%)and ethyl 7-ethyl-5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (1.2g, 8.1%) as white solids.

Ethyl 5-ethyl-7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate: LC-MSm/z: 236.1 [M+H]⁺. LCMS: t_(R)=0.93 min.

Ethyl 7-ethyl-5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate: LC-MSm/z: 236.1 [M+H]⁺. LCMS: t_(R)=1.11 min.

A mixture of ethyl5-ethyl-7-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (0.8 g, 3.4mmol) in phenylphosphonic dichloride (4 mL) was stirred at 100° C. for24 h, cooled and quenched with H₂O (100 mL). The mixture was extractedwith EtOAc (100 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, and filtered. The filtrate was concentrated in vacuo,and the residues was purified by pre-TLC (PE:EA=1:1) to afford ethyl7-chloro-5-ethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (450 mg, 52%) asa white solid, LC-MS m/z: 254.0 [M+H]⁺. LCMS: t_(R)=1.50 min.

Following general procedure F, ethyl7-chloro-5-ethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (450 mg, 1.8mmol) and 2-(tributylstannyl)pyridine afforded ethyl5-ethyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (250 mg,47%) as a yellow solid. LC-MS m/z: 297.1 [M+H]⁺. LCMS: t_(R)=1.26 min.

Following general procedure B, ethyl5-ethyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (250 mg,0.84 mmol) afforded crude5-ethyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acidsodium salt (400 mg). LC-MS m/z: 269.1 [M+H]⁺. LCMS: t_(R)=1.44 min.

Following general procedure A,5-ethyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acidsodium salt (200 mg, 0.70 mmol) and (S)-1-cyclopropylethanamine affordedthe title compound (15 mg, 6% over 2 steps) as a yellow solid ¹H NMR(400 MHz, MeOD-d₄): δ 8.76 (d, J=4.0 Hz, 1H), 8.58 (d, J=8.0 Hz, 1H),8.49 (s, 1H), 8.04 (td, J=8.0 Hz, 1.2 Hz, 1H), 7.97 (s, 1H), 7.56 (ddd,J=7.6 Hz, 4.8 Hz, 0.8 Hz, 1H), 3.74-3.67 (m, 1H), 3.21 (q, J=7.2 Hz,2H), 1.56 (t, J=7.2 Hz, 3H), 1.42 (d, J=6.8 Hz, 3H), 1.20-1.10 (m, 1H),0.67-0.54 (m, 2H), 0.52-0.45 (m, 1H), 0.42-0.35 (m, 1H). LC-MS m/z:336.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.46 min.

(S)—N-(1-Cyclopropylethyl)-7-ethyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of ethyl7-ethyl-5-hydroxypyrazolo[1,5-a]pyrimidine-3-carboxylate (1.2 g, 5.1mmol) in phenylphosphonic dichloride (4 mL) was stirred at 100° C. for24 h, cooled and quenched with H₂O (100 mL). The mixture was extractedwith EtOAc (100 mL×3). The combined organic layers were dried overanhydrous Na₂SO₄, and filtered. The filtrate was concentrated in vacuo,and the residues was purified by prep-TLC (PE:EA=1:1) to afford ethyl5-chloro-7-ethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (400 mg, 31%) asa white solid. LC-MS m/z: 254.0 [M+H]⁺. LCMS: t_(R)=1.51 min.

Following general procedure F, ethyl5-chloro-7-ethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (400 mg, 1.6mmol) and 2-(tributylstannyl)pyridine afforded ethyl7-ethyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg,43%) as a white solid. LC-MS m/z: 297.1 [M+H]⁺. LCMS: t_(R)=1.26 min.

Following general procedure B, ethyl7-ethyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg,0.67 mmol) afforded7-ethyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (350mg, contained the salts), which was used without further purification.LC-MS m/z: 269.1 [M+H]⁺. LCMS: t_(R)=1.18 min.

Following general procedure A,7-ethyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acidsodium salt (150 mg, 0.60 mmol) and (S)-1-cyclopropylethanamine affordedthe title compound (13 mg, 7% over 2 steps) as a white solid. ¹H NMR(400 MHz, MeOD-d₄): δ 8.79 (d, J=4.8 Hz, 1H), 8.60 (s, 1H), 8.54 (d,J=8.0 Hz, 1H), 8.17 (s, 1H), 8.07 (td, J=8.0 Hz, 1.6 Hz, 1H), 7.58 (ddd,J=7.6 Hz, 4.8 Hz, 0.8 Hz, 1H), 3.74-3.67 (m, 1H), 3.36 (q, J=7.2 Hz,2H), 1.55 (t, J=7.2 Hz, 3H), 1.42 (d, J=6.8 Hz, 3H), 1.20-1.13 (m, 1H),0.67-0.54 (m, 2H), 0.52-0.45 (m, 1H), 0.42-0.35 (m, 1H). LC-MS m/z:336.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.46 min.

7-Methyl-5-(pyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (35mg, 0.14 mmol) and 1,1,1-trifluoropropan-2-amine afforded the titlecompound the title compound (17 mg, 35%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.82 (d, J=4.5 Hz, 1H), 8.71 (s, 1H), 8.44 (d, J=9.0Hz, 1H), 8.42 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 8.14 (td, J=8.0 Hz, 2.0Hz, 1H), 7.64 (dd, J=7.0 Hz, 5.0 Hz, 1H), 5.01-4.96 (m, 1H), 2.91 (s,3H), 1.48 (d, J=6.5 Hz, 3H). LC-MS m/z: 350.1 [M+H]⁺. HPLC Purity (214nm): >99%; t_(R)=8.05 min.

5-Ethyl-7-(pyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-ethyl-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acidsodium salt (200 mg, 0.70 mmol) and 1,1,1-trifluoropropan-2-aminehydrochloride afforded the title compound (12 mg, 5% over 2 steps) as ayellow solid. ¹H NMR (400 MHz, MeOD-d₄): δ 8.77 (d, J=4.0 Hz, 1H), 8.54(d, J=8.0 Hz, 1H), 8.53 (s, 1H), 8.04 (td, J=8.0 Hz, 1.6 Hz, 1H), 8.01(s, 1H), 7.57 (ddd, J=7.6 Hz, 4.8 Hz, 0.8 Hz, 1H), 5.05-4.98 (m, 1H),3.22 (q, J=7.6 Hz, 2H), 1.58 (t, J=7.6 Hz, 3H), 1.54 (d, J=6.8 Hz, 3H).LC-MS m/z: 364.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.59 min.

7-Ethyl-5-(pyridin-2-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-ethyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acidsodium salt (150 mg, 0.60 mmol) and 1,1,1-trifluoropropan-2-aminehydrochloride afforded the title compound (5 mg, 3% over 2 steps) as awhite solid. ¹H NMR (400 MHz, MeOD-d₄): δ 8.80 (d, J=4.4 Hz, 1H), 8.65(s, 1H), 8.48 (d, J=8.0 Hz, 1H), 8.20 (s, 1H), 8.07 (td, J=8.0 Hz, 1.6Hz, 1H), 7.59 (ddd, J=7.6 Hz, 4.8 Hz, 0.8 Hz, 1H), 5.02-4.95 (m, 1H),3.37 (q, J=7.2 Hz, 2H), 1.56 (t, J=7.2 Hz, 3H), 1.54 (d, J=7.6 Hz, 3H).LC-MS m/z: 364.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.65 min.

5-(3-Methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.42mmol) and 3-methoxyphenylboronic acid afforded ethyl5-(3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (98mg, 75%) as a yellow solid. LC-MS m/z: 312.1 [M+H]⁺.

Following general procedure B, ethyl5-(3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (90mg, 0.29 mmol) afforded5-(3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(71 mg, 87%) as a white solid. LC-MS m/z: 284.1 [M+H]⁺.

Following general procedure A,5-(3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.10 mmol) and 1,1,1-trifluoropropan-2-amine afforded the titlecompound (18 mg, 47%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.66 (s, 1H), 8.49 (d, J=9.5 Hz, 1H), 7.97 (s, 1H), 7.82 (d, J=8.0 Hz,1H), 7.79 (s, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.19 (dd, J=8.0 Hz, 2.0 Hz,1H), 5.01-4.96 (m, 1H), 3.89 (s, 3H), 2.86 (s, 3H), 1.45 (d, J=6.5 Hz,3H). LC-MS m/z: 379.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.58min.

(S)—N-(1-Cyclopropylethyl)-5-(3-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.42mmol) and 3-fluorophenylboronic acid afforded ethyl5-(3-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (90mg, 72%) as a brown solid. LC-MS m/z: 300.1 [M+H]⁺. Purity (214nm): >90%; t_(R)=2.00 min.

Following general procedure B, ethyl5-(3-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (90mg, 0.3 mmol) afforded5-(3-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(70 mg, 98%) as a brown solid. LC-MS m/z: 272.0 [M+H]⁺. LC-MS Purity(214 nm): >99%; t_(R)=1.66 min.

Following general procedure A,5-(3-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.11 mmol) and (S)-1-cyclopropylethanamine afforded the titlecompound (21 mg, 56%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.59(s, 1H), 8.14 (t, J=8.0 Hz, 2H), 8.09 (dt, J=10.0 Hz, 2.5 Hz, 1H), 7.96(s, 1H), 7.69 (ddd, J=14.0 Hz, 8.0 Hz, 2.0 Hz, 1H), 7.47 (td, J=8.0 Hz,2.5 Hz, 1H), 3.65-3.61 (m, 1H), 2.86 (s, 3H), 1.28 (d, J=6.5 Hz, 3H),1.14-1.07 (m, 1H), 0.56-0.45 (m, 2H), 0.42-0.31 (m, 2H). LC-MS m/z:339.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.56 min.

(S)—N-(1-Cyclopropylethyl)-5-(3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.10 mmol) and (S)-1-cyclopropylethanamine afforded the titlecompound (10 mg, 29%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.55 (s, 1H), 8.15 (d, J=7.5 Hz, 1H), 7.88 (s, 1H), 7.82 (d, J=7.5 Hz,1H), 7.78 (s, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.16 (dd, J=8.0 Hz, 2.0 Hz,1H), 3.88 (s, 3H), 3.67-3.63 (m, 1H), 2.84 (s, 3H), 1.30 (d, J=5.0 Hz,3H), 1.08-1.05 (m, 1H), 0.53-0.47 (m, 2H), 0.41-0.38 (m, 1H), 0.34-0.30(m, 1H). LC-MS m/z: 351.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.46min.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.41mmol) and morpholine afforded ethyl7-methyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate (105 mg,88%) as a white solid. LC-MS m/z: 291.1 [M+H]⁺.

Following general procedure B, ethyl7-methyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate (105 mg,0.36 mmol) afforded7-methyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (90 mg,96%) as a white solid. LC-MS m/z: 263.0 [M+H]⁺.

Following general procedure A,7-methyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (35 mg,0.13 mmol) and (S)-1-cyclopropylethanamine afforded the title compound(31 mg, 70%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.17 (s,1H), 7.88 (d, J=7.6 Hz, 1H), 6.88 (s, 1H), 3.74 (t, J=4.0 Hz, 4H), 3.70(t, J=4.0 Hz, 4H), 3.54-3.48 (m, 1H), 2.62 (s, 3H), 1.20 (d, J=6.8 Hz,3H), 1.00-0.95 (m, 1H), 0.46-0.38 (m, 2H), 0.30-0.23 (m, 2H). LC-MS m/z:330.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=6.68 min.

N-(2-Cyclopropylpropan-2-yl)-7-methyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (35 mg,0.13 mmol) and 2-cyclopropylpropan-2-amine afforded the title compound(16 mg, 35%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.14 (s,1H), 7.83 (s, 1H), 6.89 (s, 1H), 3.71 (d, J=5.2 Hz, 8H), 2.61 (s, 3H),1.30 (s, 6H), 1.30-1.28 (m, 1H), 0.39-0.35 (m, 4H). LC-MS m/z: 344.1[M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.20 min.

(S)—N-(1-Cyclopropylethyl)-5-(4,4-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.42mmol), 4,4-difluoropiperidine hydrochloride (79 mg, 0.50 mmol) and Et₃Nafforded ethyl5-(4,4-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 70%) as a yellow solid. LC-MS m/z: 325.2 [M+H]⁺. HPLC: Purity(254 nm): >80%; t_(R)=1.41 min.

Following general procedure B, ethyl5-(4,4-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 0.31 mmol) afforded5-(4,4-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (70 mg, 70%) as a yellow solid. LC-MS m/z: 297.1 [M+H]⁺. Purity(254 nm): >80%; t_(R)=0.86 min.

Following general procedure A,5-(4,4-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (60 mg, 0.20 mmol) and (S)-1-cyclopropylethanamine afforded thetitle compound (30 mg, 40%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.18 (s, 1H), 7.86 (d, J=7.5 Hz, 1H), 6.99 (s, 1H), 3.87 (brs, 4H),3.54-3.49 (m, 1H), 2.62 (s, 3H), 2.15-2.06 (m, 4H), 1.20 (d, J=6.5 Hz,3H), 1.01-0.96 (m, 1H), 0.48-0.39 (m, 2H), 0.31-0.23 (m, 2H). LC-MS m/z:364.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.72 min.

(S)—N-(1-Cyclopropylethyl)-5-(3,3-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.42mmol) and 3,3-difluoropiperidine hydrochloride afforded ethyl5-(3,3-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 70%) as a yellow solid. LC-MS m/z: 325.2 [M+H]⁺. Purity (254nm): >80%; t_(R)=1.39 min.

Following general procedure B, ethyl5-(3,3-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(90 mg, 0.28 mmol) afforded5-(3,3-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (70 mg, 85%) as a yellow solid. LC-MS m/z: 297.1 [M+H]⁺. Purity(254 nm): >80%; t_(R)=0.86 min.

Following general procedure A,5-(3,3-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (60 mg, 0.20 mmol) and (S)-1-cyclopropylethanamine afforded thetitle compound (20 mg, 25%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.18 (s, 1H), 7.86 (d, J=7.5 Hz, 1H), 7.00 (s, 1H), 4.18-4.10 (m, 2H),3.80 (brs, 1H), 2.62 (s, 3H), 3.58-3.52 (m, 1H), 2.62 (s, 1H), 2.20-2.12(m, 2H), 1.79 (brs, 2H), 1.20 (d, J=6.5 Hz, 3H), 0.99-0.94 (m, 1H),0.49-0.39 (m, 2H), 0.33-0.24 (m, 2H). LC-MS m/z: 364.1 [M+H]⁺, HPLC:Purity (214 nm): >99%; t_(R)=7.50 min.

5-(3-Chloro-2-pyridinyl)-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (300 mg, 1.25mmol) and 6-chloropyridin-2-ylboronic acid afforded ethyl5-(6-chloropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(240 mg, 60%) as a yellow solid. LC-MS m/z: 317.2 [M+H]⁺.

The mixture of ethyl5-(6-chloropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(240 mg, 0.76 mmol) and (Bu₃Sn)₂O (2.3 g, 3.80 mmol) in toluene (10 mL)was stirred at 110° C. for 3 days, cooled and poured into saturatedNaHCO₃ solution (20 mL). The aqueous phase was washed with EA (5 mL×3),acidified to pH 6 with 6N HCl and extracted with EA (50 mL×3). Theorganic phases were dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo to afford5-(6-chloropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (46 mg, 23%) as a yellow solid. LC-MS m/z: 289.1 [M+H]⁺.

Following general procedure A,5-(6-chloropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (50 mg, 0.14 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (15.8 mg, 25%) as a white solid. ¹H NMR (500 MHz,MeOD-d₄): δ 8.58 (s, 1H), 8.44 (d, J=7.5 Hz, 1H), 8.37 (brs, 1H), 8.07(s, 1H), 8.01 (t, J=7.5 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 2.93 (s, 3H),1.50 (s, 6H), 1.50-1.47 (m, 1H), 0.62-0.59 (m, 4H). LC-MS m/z: 370.1[M+H]⁺. HPLC Purity (214 nm): 99%; t_(R)=11.43 min.

5-(6-Chloropyridin-2-yl)-7-methyl-N-(2-methylbut-3-yn-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(6-chloropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (50 mg, 0.14 mmol) and 2-methylbut-3-yn-2-amine afforded the titlecompound (18 mg, 30%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄): δ8.72 (brs, 1H), 8.62 (s, 1H), 8.51 (d, J=8.0 Hz, 1H), 8.13 (s, 1H), 8.05(t, J=8.0 Hz, 1H), 7.63 (d, J=8.0 Hz, 1H), 2.97 (s, 1H), 2.96 (s, 3H),1.88 (s, 6H). LC-MS m/z: 354.1 [M+H]⁺. LC-MS Purity (214 nm): >99%;t_(R)=10.66 min.

5-(3-Chlorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (300 mg, 1.25mmol) and 3-chlorophenylboronic acid afforded ethyl5-(3-chlorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (390mg, 98%) as a white solid. LC-MS m/z: 315.0 [M+H]⁺. Purity (214nm): >72%; t_(R)=2.00 min.

Following general procedure B, ethyl5-(3-chlorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (390mg, 1.24 mmol) afforded5-(3-chlorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(250 mg, 70%) as a white solid. LC-MS m/z: 287.0 [M+H]⁺. LC-MS Purity(214 nm): >80%; t_(R)=1.68 min.

Following general procedure A,5-(3-chlorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(60 mg, 0.21 mmol) and 1,1,1-trifluoropropan-2-amine afforded the titlecompound (41.8 mg, 52%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.68 (s, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.31 (t, J=2.0 Hz, 1H), 8.21 (dt,J=7.5 Hz, 1.5 Hz, 1H), 8.03 (s, 1H), 7.70-7.65 (m, 2H), 4.97 (m, J=8.0Hz, 1H), 2.87 (s, 3H), 1.45 (d, J=6.5 Hz, 3H). LC-MS m/z: 382.0 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=9.07 min.

(S)-5-(3-Chlorophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-chlorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(60 mg, 0.21 mmol) and (S)-1-cyclopropylethanamine afforded the titlecompound (38.2 mg, 51%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.58 (s, 1H), 8.33 (s, 1H), 8.23 (dd, J=8.5 Hz, 2.0 Hz, 1H), 8.15 (d,J=7.5 Hz, 1H), 7.97 (s, 1H), 7.68-7.65 (m, 2H), 3.63 (m, J=7.5 Hz, 1H),2.85 (s, 3H), 1.28 (d, J=6.5 Hz, 3H), 1.13-1.08 (m, 1H), 0.55-0.50 (m,2H), 0.40-0.33 (m, 2H). LC-MS m/z: 354.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=9.10 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3,3-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3,3-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.10 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamineafforded the title compound as a yellow solid (17 mg, 30%). ¹H NMR (500MHz, MeOD-d₄): δ 8.30 (s, 1H), 6.85 (s, 1H), 4.39 (p, J=7.5 Hz, 1H),4.20-4.18 (m, 1H), 4.09-4.05 (m, 1H), 3.92-3.88 (m, 1H), 3.85-3.81 (m,1H), 2.72 (s, 3H), 2.24-2.17 (m, 2H), 1.93-1.88 (m, 2H), 1.24-1.20 (m,1H), 0.77-0.73 (m, 1H), 0.65-0.63 (m, 1H), 0.55-0.47 (m, 2H). LC-MS m/z:418.1 [M+H]⁺. HPLC Purity (214 nm): 99%; t_(R)=8.10 min

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3,3-difluoropyrrolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.42mmol) and 3,3-difluoropyrrolidine hydrochloride (72 mg, 0.50 mmol)afforded ethyl5-(3,3-difluoropyrrolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(72 mg, 55%) as a yellow solid. LC-MS m/z: 311.2 [M+H]⁺, t_(R)=1.35 min.

Following general procedure B, ethyl5-(3,3-difluoropyrrolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(50 mg, 0.16 mmol) afforded5-(3,3-difluoropyrrolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (32 mg, 71%) as a white solid. LC-MS m/z: 283.0 [M+H]⁺. t_(R)=0.82min.

Following general procedure A,5-(3,3-difluoropyrrolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (32 mg, 0.11 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamineafforded the tile compound (4.7 mg, 10%) as a white solid. ¹H NMR (500MHz, MeOD-d₄) δ 8.30 (s, 1H), 6.52 (d, J=3.0 Hz, 1H), 4.42-4.38 (m, 1H),4.02 (t, J=12.5 Hz, 2H), 3.89 (t, J=7.5 Hz, 2H), 2.72 (s, 3H), 2.67-2.62(m, 2H), 1.28-1.20 (m, 1H), 0.78-0.74 (m, 1H), 0.68-0.60 (m, 1H),0.58-0.42 (m, 2H). LC-MS m/z: 404.1 [M+H]⁺. HPLC: Purity (254 nm): >99%;t_(R)=8.13 min.

N-(2-Cyclopropylpropan-2-yl)-7-methyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a mixture of ethyl 5-amino-1H-pyrazole-4-carboxylate (1.0 g, 6.493mmol) in AcOH (15 mL) was added 1,1,1-trifluoropentane-2,4-dione (1.0 g,6.493 mmol) at 110° C. The mixture was stirred for 2 hours andconcentrated in vacuo. The residue was dissolved in EA (100 mL). Theorganic solution was washed with 10% NaHCO₃ solution (50 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo toafford ethyl7-methyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (1.8g, 100%) as a yellow solid. LC-MS m/z: 274.0 [M+H]⁺. t_(R)=1.71 min.

To a mixture of ethyl7-methyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (100mg, 0.366 mmol) in toluene (10 mL) was added (Bu₃Sn)₂O (440 mg, 0.732mmol). The mixture was stirred at 120° C. for 2 days and concentrated invacuo. The residue was partitioned between 10% NaHCO₃ solution (20 mL)and EA (30 mL×2). The aqueous phase was acidified with 10% HCl solutionto pH at 5˜6, and extracted with EA (30 mL×2). The organic phases weredried over anhydrous Na₂SO₄, and filtered. The filtrate was concentratedin vacuo to afford7-methyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(75 mg, 83%) as a yellow solid. LC-MS m/z: 246.1 [M+H]⁺. t_(R)=1.53 min.

Following general procedure A,7-methyl-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(75 mg, 0.31 mmol) and 2-cyclopropylpropan-2-amine afforded the titlecompound (35 mg, 35%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄) δ8.56 (s, 1H), 8.26 (s, 1H), 7.60 (s, 1H), 2.98 (s, 3H), 1.45 (s, 6H),1.40-1.37 (m, 1H), 0.56-0.54 (m, 4H). LC-MS m/z: 327.1 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=8.58 min.

5-(3-Methoxyphenyl)-7-methyl-N-(2-methylbut-3-yn-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(40 mg, 0.14 mmol) and 2-methylbut-3-yn-2-amine afforded the titlecompound (36 mg, 74%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.56 (s, 1H), 8.43 (s, 1H), 7.95 (s, 1H), 7.87 (d, J=8.0 Hz, 1H), 7.81(s, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.18 (dd, J=8.5 Hz, 2.5 Hz, 1H), 3.88(s, 3H), 3.31 (s, 1H), 2.86 (s, 3H), 1.75 (s, 6H). LC-MS m/z: 349.2[M+H]⁺. LC-MS HPLC Purity (214 nm): >99%; t_(R)=8.32 min.

(S)-5-(3-Cyanophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure C,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (80 mg,0.38 mmol) and (S)-1-cyclopropylethanaminehydrochloride afforded(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamideas a yellow solid (30 mg, 28%). LC-MS m/z: 279.1 [M+H]⁺. LC-MS Purity(214 nm): 99%.

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.18 mmol) and 3-cyanophenylboronic acid afforded the titlecompound (33.4 mg, 54%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ8.72 (s, 1H), 8.44 (s, 1H), 8.33 (d, J=8.0 Hz, 1H), 8.11 (d, J=7.5 Hz,1H), 7.84 (d, J=7.5 Hz, 1H), 7.70 (t, J=8.0 Hz, 1H), 7.29 (s, 1H),3.80-3.76 (m, 1H), 2.95 (s, 3H), 1.38 (d, J=6.5 Hz, 3H), 1.08-1.04 (m,1H), 0.63-0.57 (m, 2H), 0.50-0.48 (m, 1H), 0.41-0.37 (m, 1H). LC-MS m/z:346.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.90 min.

5-(3-Cyanophenyl)-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure C,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (80 mg,0.38 mmol) and 2-cyclopropylpropan-2-amine afforded5-chloro-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(20 mg, 18%) as a yellow solid. LC-MS m/z: 293.1 [M+H]⁺. LC-MS Purity(214 nm): 91%.

Following general procedure D,5-chloro-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(40 mg, 0.14 mmol) and 3-cyanophenylboronic acid afforded the titlecompound (26.6 mg, 53%) as a white solid. 1H NMR (500 MHz, CDCl₃): δ8.71 (s, 1H), 8.47 (s, 1H), 8.34 (d, J=8.0 Hz, 1H), 8.10 (s, 1H), 7.83(d, J=8.0 Hz, 1H), 7.68 (t, J=8.0 Hz, 1H), 7.28 (s, 1H), 2.94 (s, 3H),1.58 (s, 6H), 1.43-1.39 (m, 1H), 0.60-0.57 (m, 2H), 0.55-0.53 (m, 2H).LC-MS m/z: 360.1 [M+H]⁺. LC-MS HPLC Purity (214 nm): >99%; t_(R)=8.42min.

5-(3-Cyanophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure C,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (90 mg,0.43 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlorideafforded5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(30 mg, 21%) as a yellow solid. LC-MS m/z: 333.0 [M+H]⁺. LC-MS Purity(214 nm): 89%.

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(30 mg, 0.09 mmol) and 3-cyanophenylboronic acid afforded (10.6 mg, 29%)as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.73 (s, 1H), 8.46 (d,J=8.5 Hz, 1H), 8.37 (s, 1H), 8.33 (d, J=8.5 Hz, 1H), 7.85 (d, J=8.0 Hz,1H), 7.72 (t, J=7.5 Hz, 1H), 7.33 (s, 1H), 4.53-4.48 (m, 1H), 2.96 (s,3H), 1.25-1.20 (m, 1H), 0.77-0.72 (m, 1H), 0.64-0.52 (m, 3H). LC-MS m/z:400.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.39 min.

5-(3-Carbamoylphenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (80 mg, 0.3mmol) and 3-cyanophenylboronic acid afforded ethyl5-(3-cyanophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (82mg, 89%) as a white solid. LC-MS m/z: 307.1 [M+H]⁺.

Following general procedure B, ethyl5-(3-cyanophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (82mg, 0.27 mmol) afforded5-(3-carbamoylphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (51 mg, 64%) as a yellow solid. LC-MS m/z: 279.0 [M+H]⁺.

Following general procedure A,5-(3-carbamoylphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (25 mg, 0.08 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (10.6 mg, 32%) as a yellowsolid. ¹H NMR (500 MHz, CDCl₃): δ 8.71 (s, 1H), 8.60 (s, 1H), 8.57 (d,J=8.5 Hz, 1H), 8.28 (d, J=7.5 Hz, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.68 (t,J=8.0 Hz, 1H), 7.42 (s, 1H), 4.56-4.50 (m, 1H), 3.49 (s, 2H), 2.94 (s,3H), 1.26-1.22 (m, 1H), 0.75-0.71 (m, 1H), 0.61-0.53 (m, 3H). LC-MS m/z:418.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=6.97 min.

N-(2-Cyclopropylpropan-2-yl)-5-(3-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (40mg, 0.15 mmol) and 3-fluorophenyl boronic acid afforded ethyl5-(3-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(33 mg, 67%) as a yellow solid. LC-MS m/z: 330.1 [M+H]⁺. t_(R)=2.07 min.

Following general procedure B, ethyl5-(3-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(33 mg, 0.10 mmol) afforded5-(3-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid sodium salt (30 mg, 92%) as a yellow solid. LC-MS m/z: 302.2[M+H]⁺. t_(R)=1.76 min.

Following general procedure A,5-(3-fluorophenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.10 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (1 mg, 4%) as a pale yellow solid. 1H NMR (500 MHz,DMSO-d₆): δ 8.57 (s, 1H), 8.14 (d, J=8.5 Hz, 1H), 8.13-8.10 (m, 2H),7.80 (s, 1H), 7.69-7.65 (m, 1H), 7.47 (td, J=7.5 Hz, 2.0 Hz, 1H), 5.05(s, 2H), 3.56 (s, 3H), 1.41 (s, 6H), 1.42-1.40 (m, 1H), 0.52-0.48 (m,4H). LC-MS m/z: 383.1 [M+H]⁺. LC-MS Purity (214 nm): >99%; t_(R)=10.35min.

N-(2-Cyclopropylpropan-2-yl)-7-(3-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl7-chloro-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (50mg, 0.19 mmol) and 3-fluorophenyl boronic acid afforded ethyl7-(3-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(44 mg, 72%) as a yellow solid. LC-MS m/z: 330.1 [M+H]⁺. t_(R)=1.96 min.

Following general procedure B, ethyl7-(3-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(44 mg, 0.13 mmol) afforded7-(3-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid sodium salt (40 mg, 95%) as a yellow solid. LC-MS m/z: 302.0[M+H]⁺. LCMS: t_(R)=1.76 min.

Following general procedure A,7-(3-fluorophenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (40 mg, 0.13 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (10 mg, 20%) as a white solid. 1H NMR (500 MHz, MeOD-d₄)δ 8.52 (s, 1H), 8.41 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.99 (dd, J=10.5Hz, 2.5 Hz, 1H), 7.71 (s, 1H), 7.59 (ddd, J=15.0 Hz, 7.0 Hz, 2.0 Hz,1H), 7.33 (td, J=8.5 Hz, 2.5 Hz, 1H), 5.04 (s, 2H), 3.67 (s, 3H), 1.49(s, 6H), 1.45-1.37 (m, 1H), 0.63-0.55 (m, 4H). LC-MS m/z: 383.2 [M+H]⁺.HPLC: Purity (254 nm): >99%; t_(R)=10.34 min.

5-(3-Fluorophenyl)-7-methyl-N-(2-methylbut-3-yn-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(40 mg, 0.15 mmol) and 2-methylbut-3-yn-2-amine afforded the titlecompound (24.5 mg, 50%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.58 (s, 1H), 8.46 (s, 1H), 8.15 (d, J=8.0 Hz, 1H), 8.09 (td, J=12.0 Hz,2.0 Hz, 1H), 7.98 (s, 1H), 7.71-7.66 (m, 1H), 7.46 (td, J=8.5 Hz, 2.0Hz, 1H), 3.35 (s, 1H), 2.86 (s, 3H), 1.75 (s, 6H). LC-MS m/z: 336.1[M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.42 min.

5-(3-Ethoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (150 mg, 1.25mmol) and 2-(3-ethoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneafforded ethyl5-(3-ethoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100mg, 50%) as a white solid. LC-MS m/z: 326.2 [M+1]⁺. LC-MS Purity (214nm): >96%; t_(R)=1.59 min.

Following general procedure B, ethyl5-(3-ethoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100mg, 0.31 mmol) afforded5-(3-ethoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(60 mg, 50%) as a yellow solid. LC-MS m/z: 298.1 [M+1]⁺. LC-MS Purity(214 nm): >98%; t_(R)=0.97 min.

Following general procedure A,5-(3-ethoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(50 mg, 0.17 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (30 mg, 45%) as a yellow solid. ¹H NMR (500MHz, MeOD-d₄): δ 8.60 (s, 1H), 7.75 (d, J=9.0 Hz, 1H), 7.73 (s, 1H),7.70 (s, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.14 (dd, J=8.5 Hz, 2.5 Hz, 1H),5.00 (p, J=7.5 Hz, 1H), 4.17 (qd, J=13.5 Hz, 1.5 Hz, 2H), 2.91 (s, 3H),1.53 (d, J=6.5 Hz, 3H), 1.46 (t, J=7.0 Hz, 3H). LC-MS m/z: 393.1 [M+H]⁺.HPLC Purity (214 nm): >99%; t_(R)=9.09 min.

5-(3-Cyclopropoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 0.84mmol) and2-(3-cyclopropoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneafforded ethyl5-(3-cyclopropoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(150 mg, 53%) as a yellow solid. LC-MS m/z: 338.1 [M+H]⁺. t_(R)=1.99min.

Following general procedure B, ethyl5-(3-cyclopropoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(150 mg, 0.44 mmol) afforded5-(3-cyclopropoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (100 mg, 72.9%) as a tan yellow solid. LC-MS m/z: 310.1 [M+H]⁺.LCMS: t_(R)=1.83 min

Following general procedure A,5-(3-cyclopropoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (40 mg, 0.13 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (26 mg, 50%) as a white solid. ¹H NMR (500MHz, MeOD-d₄) δ 8.61 (s, 1H), 7.83 (s, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.69(s, 1H), 7.50 (t, J=8.0 Hz, 1H), 7.31 (dd, J=8.0 Hz, 2.5 Hz, 1H),5.00-4.97 (m, 1H), 3.93-3.91 (m, 1H), 2.92 (s, 3H), 1.52 (d, J=6.0 Hz,3H), 0.88-0.85 (m, 2H), 0.78-0.76 (m, 2H). LC-MS m/z: 405.1 [M+H]⁺.HPLC: Purity (254 nm): >99%; t_(R)=9.18 min.

5-(Cyclopropylamino)-N-(dicyclopropylmethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (300 mg, 1.26mmol) and cyclopropanamine afforded ethyl5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate aslight yellow oil (215 mg, 67%). LC-MS m/z: 261.1 [M+H]⁺. t_(R)=1.59 min.

Following general procedure B, ethyl5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(215 mg, 0.83 mmol) afforded5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(146 mg, 76%) as a white solid. LC-MS m/z: 233.1 [M+H]⁺. t_(R)=0.74 min.

Following general procedure A,5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(47 mg, 0.20 mmol) and dicyclopropylmethanamine afforded the titlecompound (23 mg, 35%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.19(s, 1H), 8.16 (s, 1H), 8.11 (s, 1H), 6.20 (s, 1H), 3.40 (brs, 1H), 2.76(brs, 1H), 2.55 (s, 3H), 0.99 (d, J=6.5 Hz, 2H), 0.81 (d, J=5.5 Hz, 2H),0.56 (brs, 2H), 0.47-0.42 (m, 2H), 0.39-0.34 (m, 2H), 0.33-0.25 (m, 4H).LC-MS m/z: 326.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.47 min.

N-(2-Cyclopropylpropan-2-yl)-7-(methoxymethyl)-5-(3-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (65mg, 0.24 mmol) and 3-methoxyphenyl boronic acid afforded5-(3-methoxyphenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(57 mg, 70%) as a yellow solid. LC-MS m/z: 342.1 [M+H]⁺. t_(R)=1.01 min.

Following general procedure B, ethyl5-(3-methoxyphenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(57 mg, 0.17 mmol) at 30° C. afforded5-(3-methoxyphenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid sodium salt (46 mg, 88%) as a red solid. LC-MS m/z: 314.1 [M+H]⁺.LCMS: t_(R)=1.65 min.

Following general procedure A,5-(3-methoxyphenyl)-7-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (46 mg, 0.15 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (18.5 mg, 34%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.54 (s, 1H), 8.13 (s, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.78 (d,J=2.0 Hz, 1H), 7.74 (s, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.20 (dd, J=8.0 Hz,2.0 Hz, 1H), 5.04 (s, 3H), 3.87 (s, 3H), 3.56 (s, 3H), 1.42-1.37 (m,1H), 1.38 (s, 6H), 0.50-0.42 (m, 4H). LC-MS m/z: 395.2 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=10.23 min.

N-(2-Cyclopropylpropan-2-yl)-5-(methoxymethyl)-7-(3-methoxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl7-chloro-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (100mg, 0.37 mmol) and 3-methoxyphenyl boronic acid afforded ethyl7-(3-methoxyphenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(44 mg, 35%) as a yellow solid. LC-MS m/z: 342.1 [M+H]⁺. t_(R)=2.05 min.

Following general procedure B, ethyl7-(3-methoxyphenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(44 mg, 0.13 mmol) afforded7-(3-methoxyphenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid sodium salt (30 mg, 75%) as an orange solid. LC-MS m/z: 314.1[M+H]⁺. LCMS: t_(R)=0.95 min.

Following general procedure A,7-(3-methoxyphenyl)-5-(methoxymethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.10 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (1.6 mg, 4%) as a white solid. 1H NMR (500 MHz, MeOD-d₄)δ 8.39 (s, 1H), 8.37 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.64 (d, J=2.0 Hz,1H), 7.58 (s, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.04 (dd, J=8.0 Hz, 2.0 Hz,1H), 4.93 (s, 2H), 3.78 (s, 3H), 3.56 (s, 3H), 1.36 (s, 6H), 1.33-1.30(m, 1H), 0.49-0.42 (m, 4H). LC-MS m/z: 395.2 [M+H]⁺. HPLC: Purity (254nm): >99%; t_(R)=10.24 min.

5-(3-Methoxyphenyl)-7-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.11 mmol) and 1,1,1-trifluoro-2-methylpropan-2-amine affordedthe title compound (11 mg, 26%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.60 (s, 1H), 8.40 (s, 1H), 7.96 (s, 1H), 7.81 (d, J=7.2 Hz,1H), 7.75 (s, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.20 (dd, J=7.6 Hz, 1.6 Hz,1H), 3.88 (s, 3H), 2.86 (s, 3H), 1.73 (s, 6H). LC-MS m/z: 393.1 [M+H]⁺.LC-MS HPLC Purity (214 nm): 96%; t_(R)=8.99 min.

5-(3-Chlorophenyl)-7-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-chlorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.11 mmol) and 1,1,1-trifluoro-2-methylpropan-2-amine affordedthe title compound (9 mg, 21%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.62 (s, 1H), 8.42 (s, 1H), 8.30 (s, 1H), 8.19 (d, J=6.8 Hz,1H), 8.02 (s, 1H), 7.69-7.66 (m, 2H), 2.86 (s, 3H), 1.73 (s, 6H). LC-MSm/z: 397.0 [M+H]⁺. LC-MS Purity (254 nm): 98%; t_(R)=9.56 min.

5-(3-Fluorophenyl)-7-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(24 mg, 0.09 mmol) and 1,1,1-trifluoro-2-methylpropan-2-amine affordedthe title compound (2.6 mg, 8% over two steps) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.62 (s, 1H), 8.41 (s, 1H), 8.08 (d, J=7.6 Hz, 1H),8.03 (dt, J=10.0 Hz, 2.4 Hz, 1H), 8.00 (s, 1H), 7.69 (ddd, J=15.6 Hz,7.6 Hz, 2.0 Hz, 1H), 7.48 (td, J=8.4 Hz, 2.4 Hz, 1H), 2.86 (s, 3H), 1.72(s, 6H). LC-MS m/z: 381.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=9.10 min.

7-Ethyl-5-(pyridin-2-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-ethyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100mg, 0.40 mmol) and 1,1,1-trifluoro-2-methylpropan-2-amine afforded thetitle compound (16 mg, 13%) as a white solid. ¹H NMR (400 MHz, MeOD-d₄):δ 8.80 (d, J=4.4 Hz, 1H), 8.60 (s, 1H), 8.49 (d, J=8.0 Hz, 1H), 8.19 (s,1H), 8.05 (td, J=8.0 Hz, 1.6 Hz, 1H), 7.59 (dd, J=7.2 Hz, 5.6 Hz, 1H),3.37 (q, J=7.6 Hz, 2H), 1.82 (s, 6H), 1.55 (t, J=7.6 Hz, 3H). LC-MS m/z:378.1 [M+H]⁺. HPLC Purity (214 nm): 93%; t_(R)=9.35 min.

7-Methyl-5-(pyridin-2-yl)-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (38mg, 0.15 mmol) and 1,1,1-trifluoro-2-methylpropan-2-amine afforded thetitle compound (18.0 mg, 33%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.82 (d, J=4.5 Hz, 1H), 8.65 (s, 1H), 8.37 (d, J=8.5 Hz,1H), 8.37 (s, 1H), 8.19 (s, 1H), 8.14 (t, J=8.0 Hz, 1H), 8.64 (dd, J=7.0Hz, 4.0 Hz, 1H), 2.90 (s, 3H), 1.75 (s, 6H). LC-MS m/z: 364.2 [M+H]⁺.HPLC Purity (214 nm): >99%; t_(R)=8.77 min.

5-(2-Fluoro-5-methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.42mmol) and 2-fluoro-5-methoxyphenylboronic acid afforded ethyl5-(2-fluoro-5-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 72%) as a white solid. LCMS m/z: 330.0 [M+H]⁺. Purity (254 nm):>96%.

Following general procedure B, ethyl5-(2-fluoro-5-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 0.30 mmol) afforded5-(2-fluoro-5-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (80 mg, 89%) as a white solid. LC-MS m/z: 302.1 [M+H]⁺. Purity (254nm): >99%.

Following general procedure A,5-(2-fluoro-5-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.10 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (23.4 mg, 64%) as a white solid. ¹H NMR (400MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.44 (d, J=9.2 Hz, 1H), 7.74 (s, 1H),7.58 (dd, J=6.0 Hz, 2.8 Hz, 1H), 7.41 (dd, J=10.8 Hz, 8.8 Hz, 1H), 7.20(dt, J=8.8 Hz, 4.0 Hz, 1H), 5.00-4.93 (m, 1H), 3.85 (s, 3H), 2.88 (s,3H), 1.40 (d, J=6.8 Hz, 3H). LC-MS m/z: 397.1 [M+H]⁺. LC-MS Purity (214nm): >99%; t_(R)=8.71 min.

5-(3-Fluoro-5-methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg, 0.42mmol) and 3-fluoro-5-methoxyphenylboronic acid afforded ethyl5-(3-fluoro-5-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(130 mg, 94%) as a white solid. LCMS m/z: 330.1 [M+H]⁺. Purity (254 nm):>96%.

Following general procedure B, ethyl5-(3-fluoro-5-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(85 mg, 0.26 mmol) afforded5-(3-fluoro-5-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (48 mg, 62%) as a white solid. LC-MS m/z: 302.1 [M+H]⁺. Purity (254nm): >96%.

Following general procedure A,5-(3-fluoro-5-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (25 mg, 0.08 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (14.2 mg, 44%) as a white solid. ¹H NMR (400MHz, DMSO-d₆): δ 8.68 (s, 1H), 8.44 (d, J=9.2 Hz, 1H), 7.67-7.63 (m,2H), 7.11 (dt, J=10.8 Hz, 2.0 Hz, 1H), 5.01-4.94 (m, 1H), 3.90 (s, 3H),2.86 (s, 3H), 1.44 (d, J=6.8 Hz, 3H). LC-MS m/z: 397.1 [M+H]⁺. LC-MSPurity (214 nm): >99%; t_(R)=8.81 min.

5-(3-Chlorophenyl)-7-methyl-N-(2-methylbut-3-yn-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-chlorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.10 mmol) and 2-methylbut-3-yn-2-amine afforded the titlecompound (15.5 mg, 44%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.59 (s, 1H), 8.45 (s, 1H), 8.35 (s, 1H), 8.26 (d, J=5.2 Hz, 1H), 8.02(s, 1H), 7.683 (s, 1H), 7.676 (d, J=5.2 Hz, 1H), 3.36 (s, 1H), 2.86 (s,3H), 1.76 (s, 6H). LC-MS m/z: 353.1 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=8.94 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (300 mg, 0.83mmol) and 5-bromoisothiazole (137 mg, 0.83 mmol) afforded ethyl5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (200mg, 57%) as a yellow solid. LC-MS m/z: 289.0 [M+H]⁺. t_(R)=1.69 min.

Following general procedure B, ethyl5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (200mg, 0.69 mmol) afforded5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(150 mg, 83%) as a yellow solid. LC-MS m/z: 302.1 [M+H]⁺. t_(R)=0.91min.

Following general procedure A,5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(80 mg, 0.31 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (18 mg, 25%) as a yellowsolid. ¹H NMR (500 MHz, MeOD-d₄): δ 8.68 (s, 1H), 8.66 (s, 1H), 8.13 (s,1H), 7.77 (s, 1H), 4.48-4.42 (m, 1H), 2.96 (s, 3H), 1.40-1.31 (m, 1H),0.85-0.78 (m, 1H), 0.72-0.65 (m, 1H), 0.62-0.50 (m, 2H). LC-MS m/z:382.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=10.13 min.

5-(Isothiazol-5-yl)-7-methyl-N-(2-methylbut-3-yn-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(70 mg, 0.27 mmol) and 2-methylbut-3-yn-2-amine afforded the titlecompound (18.6 mg, 30%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄): δ8.67 (d, J=2.0 Hz, 1H), 8.60 (s, 1H), 8.10 (d, J=2.0 Hz, 1H), 7.72 (s,1H), 2.94 (s, 3H), 2.86 (s, 1H), 1.86 (s, 6H). LC-MS m/z: 326.0 [M+H]⁺.HPLC Purity (214 nm): >99%; t_(R)=9.40 min.

5-(3-Cyclopropoxyphenyl)-7-methyl-N-(2-methylbut-3-yn-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-cyclopropoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.10 mmol) and 2-methylbut-3-yn-2-amine afforded the titlecompound (22.2 mg, 61%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.56 (s, 1H), 8.45 (s, 1H), 7.93 (s, 1H), 7.90-7.88 (m, 2H), 7.56 (t,J=8.0 Hz, 1H), 7.32 (dd, J=8.0 Hz, 2.5 Hz, 1H), 4.01-3.98 (m, 1H), 3.31(s, 1H), 2.85 (s, 3H), 1.74 (s, 6H), 0.87-0.83 (m, 2H), 0.73-0.70 (m,2H). LC-MS m/z: 375.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.95min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3-(dimethylcarbamoyl)phenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and 3-(dimethylcarbamoyl)phenylboronic acid affordedthe title compound (36 mg, 45%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.68 (s, 1H), 8.58 (d, J=9.5 Hz, 1H), 8.31 (d, J=8.0 Hz,1H), 8.27 (s, 1H), 8.05 (s, 1H), 7.74 (t, J=7.5 Hz, 1H), 7.64 (d, J=7.5Hz, 1H), 4.51-4.46 (m, 1H), 3.04 (s, 3H), 2.95 (s, 3H), 2.87 (s, 3H),1.28-1.24 (m, 1H), 0.71-0.67 (m, 1H), 0.60-0.56 (m, 2H), 0.41-0.38 (m,1H). LC-MS m/z: 446.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.54min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(3-(methylcarbamoyl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and 3-(methylcarbamoyl)phenylboronic acid affordedthe title compound (13 mg, 15%) as a white solid. ¹H NMR (500 MHz,CDCl₃): δ 8.71 (s, 1H), 8.68 (s, 1H), 8.64-8.61 (m, 2H), 8.37 (d, J=7.5Hz, 1H), 8.02 (d, J=7.5 Hz, 1H), 8.017 (s, 1H), 7.72 (t, J=7.5 Hz, 1H),4.43-4.38 (m, 1H), 2.89 (s, 3H), 2.83 (d, J=4.5 Hz, 3H), 1.39-1.35 (m,1H), 0.72-0.68 (m, 1H), 0.63-0.59 (m, 2H), 0.41-0.38 (m, 1H). LC-MS m/z:432.2 [M+H]⁺. HPLC Purity (214 nm): 99%; t_(R)=7.28 min.

5-(3-(1H-Pyrazol-1-yl)phenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and 3-(1H-pyrazol-1-yl)phenylboronic acid afford thetitle compound (17 mg, 20%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆):δ 8.78 (s, 1H), 8.69 (s, 1H), 8.67-8.64 (m, 2H), 8.18 (d, J=8.0 Hz, 1H),8.09-8.08 (m, 2H), 7.78-7.75 (m, 2H), 6.62 (t, J=2.5 Hz, 1H), 4.41-4.36(m, 1H), 2.90 (s, 3H), 1.48-1.42 (m, 1H), 0.77-0.72 (m, 1H), 0.66-0.60(m, 2H), 0.42-0.37 (m, 1H). LC-MS m/z: 441.1 [M+H]⁺. HPLC Purity (254nm): 99%; t_(R)=8.73 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(3-(oxazol-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1.98 g, 8.27mmol) and 3-bromophenylboronic acid afforded ethyl5-(3-bromophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (108mg, 4%) as a brown solid. LC-MS m/z: 360.0 [M+H]⁺. t_(R)=1.63 min.

Following general procedure B, ethyl5-(3-bromophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (108mg, 0.3 mmol) afforded5-(3-bromophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(75 mg, 75%) as a light brown solid. LC-MS m/z: 332.0 [M+H]⁺. t_(R)=0.98min.

Following general procedure A,5-(3-bromophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(75 mg, 0.23 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded5-(3-bromophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(91 mg, 89%) as a light yellow solid. LC-MS m/z: 453.1 [M+H]⁺.t_(R)=1.70 min.

Following general procedure F,5-(3-bromophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(34 mg, 0.08 mmol) and 2-(tributylstannyl)oxazole afforded the titlecompound (11.2 mg, 34%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ8.89 (s, 1H), 8.68 (s, 1H), 8.65 (d, J=9.6 Hz, 1H), 8.38 (d, J=8.0 Hz,1H), 8.27 (s, 1H), 8.20 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.80 (d, J=8.0Hz, 1H), 7.44 (s, 1H), 4.46-4.36 (m, 1H), 2.89 (s, 3H), 1.45-1.37 (m,1H), 0.79-0.70 (m, 1H), 0.68-0.60 (m, 2H), 0.45-0.36 (m, 1H). LC-MS m/z:442.1 [M+H]⁺. HPLC Purity (254 nm): >99%; t_(R)=8.88 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(3-(pyrimidin-2-yl)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,5-(3-bromophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(72 mg, 0.16 mmol) and 2-(tributylstannyl)pyrimidine afforded the titlecompound (2.1 mg, 3%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.40 (s, 1H), 8.90 (d, J=4.8 Hz, 2H), 8.75 (d, J=9.6 Hz, 1H), 8.68 (s,1H), 8.61 (d, J=8.0 Hz, 1H), 8.41 (d, J=8.0 Hz, 1H), 8.06 (s, 1H), 7.79(t, J=8.0 Hz, 1H), 7.52 (t, J=4.8 Hz, 1H), 4.45-4.34 (m, 1H), 2.90 (s,3H), 1.53-1.45 (m, 1H), 0.80-0.73 (m, 1H), 0.69-0.58 (m, 2H), 0.46-0.37(m, 1H). LC-MS m/z: 453.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=9.08min.

5-(Benzo[d]oxazol-4-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(110 mg, 0.45 mmol) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (1.5 mg, 1.1%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.04 (s, 1H), 8.86 (d, J=9.5 Hz, 1H), 8.70 (s, 1H), 8.44 (s,1H), 8.31 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz,1H), 4.48-4.40 (m, 1H), 2.93 (s, 3H), 1.39-1.35 (m, 1H), 0.72-0.68 (m,1H), 0.63-0.55 (m, 2H), 0.41-0.38 (m, 1H). LC-MS m/z: 416.0 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.83 min.

5-(Benzo[d]oxazol-5-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(210 mg, 35% purity, 0.23 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (37 mg, 28%) as a yellow solid. ¹H NMR (500 MHz,MeOD-d₄) δ 8.65 (s, 1H), 8.638 (s, 1H), 8.636 (s, 1H), 8.38 (d, J=9.0Hz, 1H), 7.92 (d, J=9.0 Hz, 1H), 7.87 (s, 1H), 4.49-4.43 (m, 1H), 2.97(s, 3H), 1.39-1.33 (m, 1H), 0.83-0.78 (m, 1H), 0.72-0.66 (m, 1H),0.64-0.58 (m, 1H), 0.56-0.50 (m, 1H). LC-MS m/z: 416.1 [M+H]⁺. HPLC:Purity (214 nm): 99%; t_(R)=9.07 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(6-fluoropyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 6-fluoropyridin-3-ylboronic acid afforded thertitle compound (26 mg, 27%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆):δ 9.11 (d, J=2.5 Hz, 1H), 8.76 (td, J=8.0 Hz, 2.5 Hz, 1H), 8.70 (s, 1H),8.48 (d, J=9.5 Hz, 1H), 8.04 (s, 1H), 7.53 (dd, J=9.0 Hz, 2.5 Hz, 1H),4.46-4.40 (m, 1H), 2.88 (s, 3H), 1.34-1.29 (m, 1H), 0.71-0.67 (m, 1H),0.62-0.57 (m, 2H), 0.38-0.36 (m, 1H). LC-MS m/z: 394.1 [M+H]⁺. HPLCPurity (254 nm): 98%; t_(R)=8.39 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(2-fluoropyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.3 mmol) and 2-fluoropyridin-3-ylboronic acid afforded thetitle compound (13 mg, 11%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.74 (s, 1H), 8.60 (t, J=8.8 Hz, 1H), 8.51-8.47 (m, 2H),7.81 (s, 1H), 7.67 (d, J=6.0 Hz, 1H), 4.49-4.38 (m, 1H), 2.90 (s, 3H),1.29-1.20 (m, 1H), 0.71-0.64 (m, 1H), 0.60-0.52 (m, 2H), 0.40-0.31 (m,1H). LC-MS m/z: 394.1 [M+H]⁺. HPLC Purity (254 nm): >99%; t_(R)=8.26min.

(R)—N-(1-Cyclopropylethyl)-5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.29 mmol) and 4-fluorophenylboronic acid afforded the titlecompound (42.6 mg, 43%) as a white solid. 1H NMR (500 MHz, DMSO-d₆) δ8.56 (s, 1H), 8.33 (dd, J=8.5 Hz, 2.0 Hz, 2H), 8.16 (d, J=7.5 Hz, 1H),7.90 (d, J=1.0 Hz, 1H), 7.49 (td, J=9.0 Hz, 2.5 Hz, 2H), 3.63-3.59 (m,1H), 2.85 (s, 3H), 1.29 (d, J=6.5 Hz, 3H), 1.12-1.09 (m, 1H), 0.54-0.48(m, 2H), 0.39-0.31 (m, 2H). LC-MS m/z: 339.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.76 min.

(R)—N-(1-Cyclopropylethyl)-7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.36 mmol), and pyridin-3-ylboronic acid afforded the titlecompound (31 mg, 27%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ9.45 (d, J=2.5 Hz, 1H), 8.78 (dd, J=4.0 Hz, 1.0 Hz, 1H), 8.60 (t, J=2.0Hz, 1H), 8.59 (s, 1H), 8.12 (d, J=7.5 Hz, 1H), 7.98 (s, 1H), 7.67 (dd,J=8.0 Hz, 5.0 Hz, 1H), 3.63-3.59 (m, 1H), 2.86 (s, 3H), 1.29 (d, J=6.5Hz, 3H), 1.28-1.08 (m, 1H), 0.54-0.45 (m, 2H), 0.39-0.20 (m, 2H). LC-MSm/z: 322.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=6.93 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(100 mg, 0.39 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (47 mg, 32%) as a white solid.¹H NMR (500 MHz, MeOD-d₄) δ 9.30 (d, J=2.0 Hz, 1H), 8.65 (dd, J=4.5 Hz,1.0 Hz, 1H), 8.55 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 7.72 (s, 1H), 7.58(dd, J=8.0 Hz, 4.5 Hz, 1H), 4.35-4.28 (m, 1H), 2.86 (s, 3H), 1.24-1.18(m, 1H), 0.70-0.64 (m, 1H), 0.58-0.46 (m, 2H), 0.42-0.37 (m, 1H). LC-MSm/z: 376.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.69 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid(100 mg, 0.39 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (27 mg, 19%) as a white solid.¹H NMR (500 MHz, MeOD-d₄) δ 9.30 (d, J=2.0 Hz, 1H), 8.65 (dd, J=4.5 Hz,1.0 Hz, 1H), 8.55 (s, 1H), 8.53 (d, J=8.5 Hz, 1H), 7.72 (s, 1H), 7.58(dd, J=8.0 Hz, 4.5 Hz, 1H), 4.35-4.28 (m, 1H), 2.86 (s, 3H), 1.24-1.18(m, 1H), 0.70-0.64 (m, 1H), 0.58-0.46 (m, 2H), 0.42-0.37 (m, 1H). LC-MSm/z: 376.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.69 min.

(R)-5-(3-Methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (422 mg, 2mmol) and (R)-1,1,1-trifluoropropan-2-amine hydrochloride afforded(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(489 mg, 80%) as a pale yellow solid. LC-MS m/z: 307.0 [M+H]⁺. Purity(254 nm): 98.7%; t_(R)=1.78 min.

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(45 mg, 0.15 mmol) and 3-methoxyphenylboronic acid afforded the titlecompound (15 mg, 26%) as a white solid. 1H NMR (500 MHz, DMSO-d₆) δ 8.66(s, 1H), 8.49 (d, J=9.0 Hz, 1H), 7.98 (s, 1H), 7.83 (d, J=7.5 Hz, 1H),7.80 (s, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.19 (dd, J=8.0 Hz, 2.5 Hz, 1H),5.01-4.96 (m, 1H), 3.89 (s, 3H), 2.87 (s, 3H), 1.44 (d, J=7.0 Hz, 3H).LC-MS m/z: 379.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.81 min.

(S)-5-(3-Methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (515 mg,2.43 mmol) and (S)-1,1,1-trifluoropropan-2-amine hydrochloride afforded(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(371 mg, 50%) as a white solid. LC-MS m/z: 307.0 [M+H]⁺. t_(R)=1.79 min.

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.2 mmol) and 3-methoxyphenylboronic acid afforded the titlecompound (53 mg, 72%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67(s, 1H), 8.50 (d, J=9.5 Hz, 1H), 7.98 (s, 1H), 7.83 (d, J=7.5 Hz, 1H),7.80 (s, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.20 (dd, J=8.0 Hz, 2.0 Hz, 1H),5.00-4.97 (m, 1H), 3.89 (s, 3H), 2.87 (s, 3H), 1.45 (d, J=7.0 Hz, 3H).LC-MS m/z: 379.1 [M+H]⁺. HPLC: Purity (214 nm): 99%; t_(R)=8.81 min.

(R)—N-(1-Cyclopropylethyl)-5-(3-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.29 mmol) and 3-fluorophenylboronic acid afforded the titlecompound (53 mg, 54%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.59(s, 1H), 8.14 (t, J=9.0 Hz, 2H), 8.09 (dt, J=10.5 Hz, 1.5 Hz, 1H), 7.96(s, 1H), 7.69 (dd, J=14.5 Hz, 8.0 Hz, 1H), 7.47 (td, J=8.5 Hz, 2.5 Hz,1H), 3.66-3.61 (m, 1H), 2.86 (s, 3H), 1.28 (d, J=6.0 Hz, 3H), 1.11-1.09(m, 1H), 0.55-0.48 (m, 2H), 0.41-0.38 (m, 1H), 0.36-0.33 (m, 1H). LC-MSm/z: 339.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.79 min.

(R)-5-(3-Cyanophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.21 mmol) and 3-cyanophenylboronic acid afforded the titlecompound (44 mg, 60%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.71 (t, J=1.5 Hz, 1H), 8.61 (s, 1H), 8.59 (dt, J=8.0 Hz, 1.0 Hz, 1H),8.13 (d, J=7.5 Hz, 1H), 8.08 (dt, J=7.5 Hz, 1.0 Hz, 1H), 8.04 (s, 1H),7.86 (t, J=7.5 Hz, 1H), 3.64-3.60 (m, 1H), 2.87 (s, 3H), 1.29 (d, J=6.5Hz, 3H), 1.16-1.11 (m, 1H), 0.55-0.50 (m, 2H), 0.41-0.34 (m, 2H). LC-MSm/z: 346.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.11 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3,3-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(20 mg, 0.06 mmol) and 3,3-difluoropiperidine hydrochloride afforded thetitle compound (12 mg, 48%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.26 (s, 1H), 8.25 (d, J=9.5 Hz, 1H), 7.05 (s, 1H), 4.45-4.40 (m, 1H),4.16-4.10 (m, 2H), 3.82-3.77 (m, 2H), 2.63 (s, 3H), 2.20-2.11 (m, 2H),1.81-1.74 (m, 2H), 1.89-1.12 (m, 1H), 0.68-0.62 (m, 1H), 0.57-0.47 (m,2H), 0.36-0.32 (m, 1H). LC-MS m/z: 418.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.32 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3,3-difluoropiperidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(25 mg, 0.06 mmol) and 3,3-difluoropiperidine hydrochloride afforded thetitle compound (28 mg, 89%) as a white solid. 1H NMR (500 MHz, DMSO-d₆)δ 8.27 (s, 1H), 8.25 (s, 1H), 7.05 (s, 1H), 4.43 (q, J=8.0 Hz, 1H), 4.13(td, J=12.0 Hz, 2.5 Hz, 2H), 3.79 (s, 2H), 2.63 (s, 3H), 2.20-2.12 (m,2H), 1.80-1.76 (m, 2H), 1.18-1.13 (m, 1H), 0.68-0.62 (m, 1H), 0.57-0.48(m, 2H), 0.37-0.32 (m, 1H). LC-MS m/z: 418.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.33 min.

5-(3-Methoxyphenyl)-7-methyl-N-(1,1,1-trifluorobut-3-yn-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(40 mg, 0.14 mmol) and 1,1,1-trifluorobut-3-yn-2-amine afforded thetitle compound (7.0 mg, 9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.94 (d, J=11.2 Hz, 1H), 8.70 (s, 1H), 8.01 (s, 1H), 7.84 (d, J=8.0Hz, 1H), 7.82-7.80 (m, 1H), 7.54 (t, J=8.0 Hz, 1H), 7.20 (dd, J=8.0 Hz,1.2 Hz, 1H), 6.05-5.95 (m, 1H), 3.88 (s, 3H), 3.87 (d, J=3.0 Hz, 1H),2.86 (s, 3H). LC-MS m/z: 389.1 [M+H]⁺. HPLC: Purity (214 nm): 98%;t_(R)=8.86 min.

(R)-5-(2-Fluoro-5-methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(62 mg, 0.2 mmol) and 2-fluoro-5-methoxyphenylboronic acid afforded thetitle compound (50 mg, 63%) as a white solid. 1H NMR (500 MHz, DMSO-d₆)δ 8.70 (s, 1H), 8.44 (d, J=9.5 Hz, 1H), 7.73 (s, 1H), 7.58 (q, J=3.0 Hz,1H), 7.41 (dd, J=11.5 Hz, 9.5 Hz, 1H), 7.20 (dt, J=9.0 Hz, 3.5 Hz, 1H),4.98-4.94 (m, 1H), 3.85 (s, 3H), 2.88 (s, 3H), 1.40 (d, J=7.0 Hz, 3H).LC-MS m/z: 397.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.93 min.

(S)-5-(2-Fluoro-5-methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(90 mg, 0.29 mmol) and 2-fluoro-5-methoxyphenylboronic acid afforded thetitle compound (67 mg, 58%) as a white solid. 1H NMR (500 MHz, DMSO-d₆)δ 8.71 (s, 1H), 8.44 (d, J=9.5 Hz, 1H), 7.74 (s, 1H), 7.58 (q, J=3.0 Hz,1H), 7.41 (dd, J=11.5 Hz, 9.5 Hz, 1H), 7.20 (dt, J=9.0 Hz, 3.5 Hz, 1H),5.00-4.93 (m, 1H), 3.85 (s, 3H), 2.88 (s, 3H), 1.41 (d, J=7.5 Hz, 3H).LC-MS m/z: 397.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.96 min.

5-(3-Chlorophenyl)-7-methyl-N-(1,1,1-trifluorobut-3-yn-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-chlorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(100 mg, 0.35 mmol) and 1,1,1-trifluorobut-3-yn-2-amine afforded thetitle compound (44.3 mg, 27%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.94 (d, J=9.0 Hz, 1H), 8.74 (s, 1H), 8.31 (s, 1H), 8.22 (d,J=8.0 Hz, 1H), 8.06 (s, 1H), 7.70 (d, J=8.0 Hz, 1H), 7.67 (t, J=8.0 Hz,1H), 6.02-5.97 (m, 1H), 3.87 (t, J=2.5 Hz, 1H), 2.87 (s, 3H). LC-MS m/z:393.1 [M+H]⁺. LC-MS Purity (214 nm): >99%; t_(R)=9.24 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(75 mg, 0.226 mmol) and 5-bromoisothiazole afforded the title compound(4.3 mg, 5%) as a light yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.81(s, 1H), 8.71 (s, 1H), 8.28 (s, 1H), 8.26 (d, J=10.0 Hz, 1H), 7.98 (s,1H), 4.50-4.45 (m, 1H), 2.87 (s, 3H), 1.31-1.29 (m, 1H), 0.71-0.57 (m,3H), 0.43-0.41 (m, 1H). LC-MS m/z: 382.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.34 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and 5-bromoisothiazole afforded the title compound(35 mg, 31%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.81 (d,J=1.5 Hz, 1H), 8.72 (s, 1H), 8.28 (d, J=1.5 Hz, 1H), 8.27 (d, J=9.5 Hz,1H), 7.98 (s, 1H), 4.50-4.47 (m, 1H), 2.87 (s, 3H), 1.32-1.27 (m, 1H),1.07-1.03 (m, 1H), 0.73-0.56 (m, 3H), 0.45-0.40 (m, 1H). LC-MS m/z:382.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.33 min.

5-(3-(1H-Imidazol-2-yl)phenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of5-(3-cyanophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.18 mmol), NaOMe (28 mg, 0.53 mmol) in MeOH (15 mL) was stirredat 40° C. for 16 h then 2,2-dimethoxyethanamine (21 mg, 0.21 mmol) andAcOH (420 mg, 7 mmol) were added and the mixture was stirred at 65° C.for 2 h. Then 6N HCl (1.4 mL) was added and the mixture was stirred at80° C. for 16 h, cooled and the resulting slurry was filtered and thefiltrate concentrated in vacuo. The residue was purified by preparativeHPLC (MeCN/NH₄HCO₃) to afford the title compound (2.5 mg, 2%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.91 (s, 1H), 8.71 (d, J=9.6 Hz,1H), 8.68 (s, 1H), 8.19 (d, J=7.2 Hz, 1H), 8.11 (d, J=7.2 Hz, 1H), 7.98(s, 1H), 7.71 (t, J=7.2 Hz, 1H), 7.34 (s, 1H), 7.04 (s, 1H), 4.38-4.30(m, 1H), 2.90 (s, 3H), 1.570-1.48 (m, 1H), 0.78-0.60 (m, 3H), 0.43-0.35(m, 1H). LC-MS m/z: 441.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.53min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(3-(pyrimidin-2-yloxy)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (572 mg, 2.39mmol) and 2-(3-bromophenoxy)pyrimidine afforded ethyl7-methyl-5-(3-(pyrimidin-2-yloxy)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(101 mg, 22%) as a yellow solid. LC-MS m/z: 376.1 [M+H]⁺. LC-MS Purity(214 nm): >96%; t_(R)=1.71 min.

To a solution of ethyl7-methyl-5-(3-(pyrimidin-2-yloxy)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(86 mg, 0.23 mmol) in toluene (2 mL) was added bis(tri-n-butyltin) oxide(273 mg, 0.46 mmol). The mixture was heated at 100° C. for 10 days, andconcentrate in vacuo. The residue was purified by flash chromatographyon silica gel (0 to 10% MeOH/EA) to afford7-methyl-5-(3-(pyrimidin-2-yloxy)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (39 mg, 49%) as a yellow solid. LC-MS m/z: 343.1 [M+H]⁺. LC-MSPurity (214 nm): >93%; t_(R)=1.46 min.

Following general procedure A,7-methyl-5-(3-(pyrimidin-2-yloxy)phenyl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (36 mg, 0.10 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (1.5 mg, 3%) as a yellowsolid. ¹H NMR (500 MHz, MeOD-d₄): δ 8.65 (d, J=4.5 Hz, 2H), 8.62 (s,1H), 8.17 (d, J=8.0 Hz, 1H), 8.11 (s, 1H), 7.82 (s, 1H), 7.71 (t, J=8.0Hz, 1H), 7.46 (dd, J=8.5 Hz, 2.0 Hz, 1H), 7.28 (t, J=4.5 Hz, 1H),4.43-4.38 (m, 1H), 2.95 (s, 3H), 1.13-1.06 (m, 1H), 0.71-0.67 (m, 1H),0.62-0.51 (m, 2H), 0.49-0.44 (m, 1H). LC-MS m/z: 469.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.17 min.

5-(Benzo[d]oxazol-7-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 7-bromobenzo[d]oxazole (500 mg, 2.53 mmol), sodium2-ethylhexanoate (1.05 g, 6.325 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (771 mg, 3.1mmol), and Pd(dppf)Cl₂.CH₂Cl₂ (206 mg, 0.253 mmol) in toluene (15 mL)was stirred at 110° C. for 16 h, and concentrated in vacuo to affordcrude 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole(2.5 g) as a yellow oil, which was used in the next step without furtherpurifications. LC-MS m/z: 255.1 [M+H]⁺; t_(R)=0.74 min.

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.3 mmol) and crude7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole (800 mg)afforded the title compound (33.6 mg, 10%) as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.92 (s, 1H), 8.72 (s, 1H), 8.71 (d, J=8.0 Hz, 1H),8.28 (d, J=8.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.67 (t,J=8.0 Hz, 1H), 4.48-4.43 (m, 1H), 2.92 (s, 3H), 1.34-1.32 (m, 1H)0.72-0.70 (m, 1H), 0.62-0.58 (m, 2H), 0.38-0.36 (m, 1H). LC-MS m/z:416.1 [M+H]⁺. LC-MS Purity (214 nm): 98%; t_(R)=8.34 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(6-methoxypyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 0.84mmol) and 2-methoxy-6-(tributylstannyl)pyridine afforded ethyl5-(6-methoxypyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(220 mg, 84%) as a yellow solid. LC-MS m/z: 313.1 [M+H]⁺. Purity (214nm): 79.4%; t_(R)=1.87 min.

Following general procedure B*, ethyl5-(6-methoxypyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(200 mg, 0.64 mmol) afforded5-(6-methoxypyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (154 mg, 84%). LC-MS m/z: 285.1 [M+H]⁺. Purity (214 nm): 54.51%;t_(R)=1.26 min.

Following general procedure A,5-(6-methoxypyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (120 mg, 0.53 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (94 mg, 47%) as a yellowsolid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.56 (d, J=9.5 Hz,1H), 8.18 (s, 1H), 8.04-8.04 (m, 2H), 7.08 (dd, J=7.0 Hz, 2.0 Hz, 1H),4.48-4.42 (m, 1H), 4.07 (s, 3H), 2.92 (s, 3H), 1.40-1.31 (m, 1H),0.72-0.65 (m, 1H), 0.63-0.58 (m, 2H), 0.42-0.38 (m, 1H). LC-MS m/z:406.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=9.46 min.

5-(3-Chloro-1H-pyrazol-1-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(166 mg, 0.5 mmol) and 3-chloro-1H-pyrazole afforded the title compound(45 mg, 19%) as an off-white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.72 (d,J=3.0 Hz, 1H), 4.33-4.28 (m, 1H), 2.88 (s, 3H), 1.46-1.40 (m, 1H),0.73-0.68 (m, 1H), 0.62-0.52 (m, 2H), 0.40-0.35 (m, 1H). LC-MS m/z:399.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=9.16 min.

(R)-5-(Benzo[d]oxazol-5-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.22 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (63 mg, 67%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.92 (s, 1H), 8.70 (d, J=1.6 Hz, 1H), 8.67 (s, 1H), 8.64 (d,J=5.6 Hz, 1H), 8.36 (dd, J=8.8 Hz, 1.6 Hz, 1H), 8.11 (s, 1H), 8.05 (d,J=8.8 Hz, 1H), 4.52-4.46 (m, 1H), 2.88 (s, 3H), 1.33-1.27 (m, 1H),0.73-0.67 (m, 1H), 0.63-0.56 (m, 2H), 0.45-0.40 (m, 1H). LC-MS m/z:416.1 [M+H]⁺. HPLC: Purity (214 nm): 97.37%; t_(R)=8.33 min.

(S)-5-(Benzo[d]oxazol-5-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.22 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (63 mg, 67%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.91 (s, 1H), 8.70 (d, J=1.5 Hz, 1H), 8.67 (s, 1H), 8.62 (d,J=9.0 Hz, 1H), 8.36 (dd, J=8.5 Hz, 2.0 Hz, 1H), 8.10 (s, 1H), 8.05 (d,J=8.0 Hz, 1H), 4.52-4.46 (m, 1H), 2.88 (s, 3H), 1.33-1.27 (m, 1H),0.73-0.67 (m, 1H), 0.63-0.56 (m, 2H), 0.45-0.40 (m, 1H). LC-MS m/z:416.1 [M+H]⁺. HPLC: Purity (214 nm): 97.37%; t_(R)=8.33 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(55 mg, 0.20 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (5.4 mg, 7%) as a yellowsolid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.69 (s, 1H), 8.56 (d, J=9.5 Hz,1H), 8.10 (d, J=8.0 Hz, 1H), 8.05 (d, J=10.5 Hz, 1H), 8.02 (s, 1H), 7.79(dd, J=14.0 Hz, 8.0 Hz, 1H), 7.49 (td, J=8.5 Hz, 2.5 Hz, 1H), 4.53-4.45(m, 1H), 2.87 (s, 3H), 1.31-1.26 (m, 1H), 0.71-0.66 (m, 1H), 0.61-0.55(m, 2H), 0.42-0.38 (m, 1H). LC-MS m/z: 393.2 [M+H]⁺. HPLC Purity (214nm): 95%; t_(R)=9.17 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(6-fluoropyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 6-fluoropyridin-3-ylboronic acid afforded thetitle compound (25.7 mg, 27%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.11 (d, J=2.5 Hz, 1H), 8.76 (td, J=8.0 Hz, 2.5 Hz, 1H),8.70 (s, 1H), 8.48 (d, J=9.5 Hz, 1H), 8.04 (s, 1H), 7.53 (dd, J=9.0 Hz,2.5 Hz, 1H), 4.46-4.40 (m, 1H), 2.88 (s, 3H), 1.34-1.29 (m, 1H),0.71-0.67 (m, 1H), 0.62-0.57 (m, 2H), 0.38-0.36 (m, 1H). LC-MS m/z:394.1 [M+H]⁺. HPLC Purity (254 nm): 98%; t_(R)=8.39 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(2-fluoropyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (300 mg,1.42 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlorideafforded(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(300 mg, 67%) as a white solid. LC-MS m/z: 333.1 [M+H]⁺. HPLC: Purity(214 nm): >95%; t_(R)=1.84 min.

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 2-fluoropyridin-3-ylboronic acid afforded thetitle compound (15 mg, 16%) as a white solid. 1H NMR (400 MHz, DMSO-d₆)δ 8.73 (s, 1H), 8.60 (t, J=8.0 Hz, 1H), 8.50-8.47 (m, 2H), 7.80 (s, 1H),7.67 (t, J=6.0 Hz, 1H), 4.46-4.40 (m, 1H), 2.89 (s, 3H), 1.27-1.19 (m,1H), 0.70-0.64 (m, 1H), 0.60-0.52 (m, 2H), 0.39-0.33 (m, 1H). LC-MS m/z:394.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.37 min

(S)—N-(1-cyclopropyl-2,2,2-trifluoroethyl)-5-(2-fluoropyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (844 mg,4.0 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlorideafforded(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(940 mg, 71%) as a white solid. LC-MS m/z: 333.1 [M+H]⁺. t_(R)=1.83 min.

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(1.8 g, 5.4 mmol) and 2-fluoropyridin-3-ylboronic acid afforded thetitle compound (1.5 g, 69%) as a white solid. ¹H NMR (400 MHz, MeOD-d₄)δ 8.68 (s, 1H), 8.63 (tt, J=10.0 Hz, 2.0 Hz, 1H), 8.44 (dd, J=2.8 Hz,1.2 Hz, 1H), 7.71 (s, 1H), 7.59 (tt, J=10.0 Hz, 2.0 Hz, 1H), 4.42-4.39(m, 1H), 2.97 (s, 3H), 1.31-1.26 (m, 1H), 0.79-0.74 (m, 1H), 0.65-0.57(m, 2H), 0.51-0.48 (m, 1H). LC-MS m/z: 394.1[M+H]⁺. HPLC: Purity (214nm): 99%; t_(R)=8.40 min.

(R)-5-(6-Chloropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (550 mg,2.48 mmol), and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(735 mg, 88%) as a white solid. LC-MS m/z: 333.0 [M+H]⁺. Purity (214nm): >99%; t_(R)=1.86 min.

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.21 mmol) and 6-chloropyridin-3-ylboronic acid afforded thetitle compound (18 mg, 20%) as an off-white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.25 (d, J=2.0 Hz, 1H), 8.71 (s, 1H), 8.61 (dd, J=8.0 Hz, 1.5Hz, 1H), 8.46 (d, J=9.5 Hz, 1H), 8.04 (s, 1H), 7.85 (d, J=8.0 Hz, 1H),4.46-4.38 (m, 1H), 2.88 (s, 3H), 1.34-1.31 (m, 1H), 0.73-0.68 (m, 1H),0.62-0.57 (m, 2H), 0.40-0.35 (m, 1H). LC-MS m/z: 410.1 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=8.80 min.

(S)-5-(6-Chloropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (300 mg,1.42 mmol), and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(355 mg, 75%) as a white solid. LC-MS m/z: 333.0 [M+H]⁺. Purity (214nm): >99%; t_(R)=1.86 min.

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 6-chloropyridin-3-ylboronic acid afforded thetitle compound (17.5 mg, 24%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.24 (d, J=2.0 Hz, 1H), 8.71 (s, 1H), 8.61 (dd, J=8.5 Hz, 2.5Hz, 1H), 8.45 (d, J=9.5 Hz, 1H), 8.04 (s, 1H), 7.84 (d, J=8.0 Hz, 1H),4.46-4.38 (m, 1H), 2.88 (s, 3H), 1.34-1.31 (m, 1H), 0.72-0.67 (m, 1H),0.61-0.59 (m, 2H), 0.40-0.36 (m, 1H). LC-MS m/z: 410.0 [M+H]⁺. HPLC:Purity (214 nm): >98%; t_(R)=8.79 min.

(R)-5-(5-Chloropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 5-chloropyridin-3-ylboronic acid afforded thetitle compound (5.5 mg, 6%) as a white solid. 1H NMR (400 MHz, DMSO-d₆)δ 9.38 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.4 Hz, 1H), 8.72 (s, 1H), 8.70 (t,J=2.0 Hz, 1H), 8.48 (d, J=12.8 Hz, 1H), 8.12 (s, 1H), 4.50-4.46 (m, 1H),2.88 (s, 3H), 1.32-1.26 (m, 1H), 0.72-0.67 (m, 1H), 0.61-0.56 (m, 2H),0.43-0.37 (m, 1H). LC-MS m/z: 410.0 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.73 min.

(S)-5-(5-Chloropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 5-chloropyridin-3-ylboronic acid afforded thetitle compound (33 mg, 44%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 9.39 (d, J=1.5 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.73 (s, 1H), 8.71 (s,1H), 8.48 (d, J=9.5 Hz, 1H), 8.12 (s, 1H), 4.53-4.44 (m, 1H), 2.89 (s,3H), 1.33-1.26 (m, 1H), 0.74-0.67 (m, 1H), 0.62-0.57 (m, 2H), 0.45-0.39(m, 1H). LC-MS m/z: 410.0 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.71 min.

5-(4-Chloropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 4-chloropyridin-3-ylboronic acid afforded thetitle compound (5.5 mg, 6%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.97 (s, 1H), 8.76 (s, 1H), 8.72 (d, J=4.5 Hz, 1H), 8.40 (d, J=9.5 Hz,1H), 7.83 (d, J=5.5 Hz, 1H), 7.75 (s, 1H), 4.45-4.36 (m, 1H), 2.89 (s,3H), 1.20-1.12 (m, 1H), 0.68-0.62 (m, 1H), 0.59-0.48 (m, 2H), 0.34-0.28(m, 1H). LC-MS m/z: 410.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.10 min.

5-(2-Chloropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.21 mmol) and 2-chloropyridin-3-ylboronic acid afforded thetitle compound (12 mg, 15%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ 8.75 (s, 1H), 8.62 (dd, J=4.8 Hz, 1.6 Hz, 1H), 8.41 (d, J=9.6 Hz, 1H),8.26 (dd, J=7.6 Hz, 1.6 Hz, 1H), 7.71 (t, J=6.0 Hz, 1H), 4.44-4.36 (m,1H), 2.89 (s, 3H), 1.21-1.12 (m, 1H), 0.69-0.61 (m, 1H), 0.59-0.47 (m,2H), 0.34-0.27 (m, 1H). LC-MS m/z: 410.1 [M+H]⁺. HPLC Purity (214nm): >99%; t_(R)=8.24 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4-fluoropyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 4-fluoropyridin-3-ylboronic acid afforded thetitle compound (7.7 mg, 11%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 9.21 (d, J=10.8 Hz, 1H), 8.80 (dd, J=8.0 Hz, 6.0 Hz, 1H),8.74 (s, 1H), 8.47 (d, J=9.6 Hz, 1H), 7.81 (s, 1H), 7.64 (dd, J=7.6 Hz,6.0 Hz, 1H), 4.49-4.42 (m, 1H), 2.89 (s, 3H), 1.23-1.18 (m, 1H),0.68-0.64 (m, 1H), 0.59-0.54 (m, 2H), 0.39-0.34 (m, 1H). LC-MS m/z:394.0 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.81 min.

(R)-5-(5-Fluoropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 5-fluoropyridin-3-ylboronic acid afforded thetitle compound (4.2 mg, 5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.38 (d, J=1.6 Hz, 1H), 8.87 (d, J=1.6 Hz, 1H), 8.72 (s, 1H), 8.70 (t,J=2.4 Hz, 1H), 8.48 (d, J=10.0 Hz, 1H), 8.12 (s, 1H), 4.51-4.45 (m, 1H),2.88 (s, 3H), 1.32-1.24 (m, 1H), 0.72-0.66 (m, 1H), 0.62-0.55 (m, 2H),0.43-0.37 (m, 1H). LC-MS m/z: 394.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.25 min.

(S)-5-(5-Fluoropyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 5-fluoropyridin-3-ylboronic acid afforded thetitle compound (25 mg, 35%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 9.32 (s, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.73 (s, 1H), 8.49-8.48 (m, 2H),8.09 (s, 1H), 4.51-4.43 (m, 1H), 2.89 (s, 3H), 1.35-1.28 (m, 1H),0.73-0.67 (m, 1H), 0.63-0.56 (m, 2H), 0.44-0.37 (m, 1H). LC-MS m/z:394.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.34 min.

(S)-5-(3-Cyano-5-fluorophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.29 mmol) and 3-cyano-5-fluorophenylboronic acid afforded thetitle compound (25 mg, 25%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆)δ 8.63 (s, 1H), 8.61 (s, 1H), 8.46 (d, J=9.6 Hz, 1H), 8.13 (d, J=8.0 Hz,1H), 8.08 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 3.66-3.60 (m, 1H), 2.87 (s,3H), 1.28 (d, J=6.4 Hz, 3H), 1.16-1.12 (m, 1H), 0.55-0.48 (m, 2H),0.43-0.34 (m, 2H). LC-MS m/z: 364.1 [M+H]⁺. HPLC: Purity (214 nm): >98%;t_(R)=8.36 min.

(S)-5-(3-Cyano-5-methoxyphenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(78 mg, 0.28 mmol) and3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileafforded the title compound (54 mg, 51%) as an off-white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 8.60 (s, 1H), 8.27 (s, 1H), 8.11-7.98 (m, 3H),7.69 (s, 1H), 3.95 (s, 3H), 3.64-3.60 (m, 1H), 2.85 (s, 3H), 1.29 (d,J=6.4 Hz, 3H), 1.11-1.07 (m, 1H), 0.59-0.42 (m, 2H), 0.42-0.36 (m, 1H),0.36-0.29 (m, 1H). LC-MS m/z: 376.1 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=8.38 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(6-fluoropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 2-fluoro-6-(tributylstannyl)pyridine afforded thetitle compound (37 mg, 39%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.73 (s, 1H), 8.50 (d, J=9.5 Hz, 1H), 8.34-8.30 (m, 2H),8.04 (s, 1H), 7.45 (dd, J=8.5 Hz, 4.5 Hz, 1H), 4.46-4.40 (m, 1H), 2.91(s, 3H), 1.40-1.35 (m, 1H), 0.74-0.68 (m, 1H), 0.64-0.58 (m, 2H),0.45-0.40 (m, 1H). LC-MS m/z: 394.1 [M+H]⁺. HPLC Purity (214 nm): 99%;t_(R)=9.00 min.

(S)-5-(6-Chloropyridin-2-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(150 mg, 0.54 mmol) and2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineafforded the title compound (73 mg, 37%) as a yellow solid. ¹H NMR (400MHz, MeOD-d₄): δ 8.61 (s, 1H), 8.46 (d, J=8.0 Hz, 1H), 8.11 (s, 1H),8.05 (t, J=8.0 Hz, 1H), 7.62 (d, J=8.0 Hz, 1H), 3.70-3.65 (m, 1H), 2.94(s, 3H), 1.42 (d, J=8.0 Hz, 3H), 1.19-1.14 (m, 1H), 0.66-0.58 (m, 2H),0.50-0.46 (m, 1H), 0.41-0.36 (m, 1H). LC-MS m/z: 369.1 [M+H]⁺. HPLCPurity (214 nm): 99%; t_(R)=8.62 min.

(R)-5-(6-Chloropyridin-2-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.21 mmol) and2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineafforded the title compound (31 mg, 60%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.45 (d, J=7.5 Hz, 1H), 8.20 (t, J=8.0 Hz,1H), 8.07 (d, J=8.0 Hz, 1H), 8.02 (s, 1H), 7.76 (d, J=8.0 Hz, 1H),3.62-3.58 (m, 1H), 2.91 (s, 3H), 1.32 (d, J=6.5 Hz, 3H), 1.16-1.14 (m,1H), 0.54-0.48 (m, 2H), 0.40-0.32 (m, 2H). LC-MS m/z: 356.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=9.03 min.

5-(6-Cyanopyridin-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 6-cyanopyridin-2-ylboronic acid afforded thetitle compound (42 mg, 44%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.74 (s, 1H), 8.65 (d, J=8.0 Hz, 1H), 8.47 (d, J=9.2 Hz,1H), 8.39 (t, J=8.0 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 8.14 (s, 1H),4.41-4.37 (m, 1H), 2.92 (s, 3H), 1.40-1.36 (m, 1H), 0.72-0.67 (m, 1H),0.64-0.57 (m, 2H), 0.40-0.37 (m, 1H). LC-MS m/z: 401.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.65 min.

(S)—N-(1-Cyclopropylethyl)-5-(6-fluoropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.28 mmol) and 2-fluoro-6-(tributylstannyl)pyridine afforded thetitle compound (55 mg, 56%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.62 (s, 1H), 8.40 (dd, J=7.5 Hz, 2.0 Hz, 1H), 8.32 (dd,J=16.0 Hz, 8.0 Hz, 1H), 8.07 (d, J=7.5 Hz, 1H), 7.99 (s, 1H), 7.44 (dd,J=8.0 Hz, 2.0 Hz, 1H), 3.64-3.58 (m, 1H), 2.89 (s, 3H), 1.33 (d, J=6.5Hz, 3H), 1.18-1.12 (m, 1H), 0.58-0.49 (m, 2H), 0.41-0.36 (m, 1H),0.36-0.31 (m, 1H). LC-MS m/z: 340.1 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=8.45 min.

(R)—N-(1-Cyclopropylethyl)-5-(6-fluoropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.0 g,4.74 mmol) and (R)-1-cyclopropylethanamine afforded(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(1.2 g, 90%) as a white solid.

Following general procedure F,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.29 mmol), and 2-fluoro-6-(tributylstannyl)pyridine affordedthe title compound (24.3 mg, 25%) as a white solid. 1H NMR (400 MHz,DMSO-d₆): δ 8.64 (s, 1H), 8.42 (dd, J=7.6 Hz, 2.0 Hz, 1H), 8.32 (q,J=8.0 Hz, 1H), 8.09 (d, J=7.2 Hz, 1H), 8.01 (s, 1H), 7.45 (dd, J=8.0 Hz,2.0 Hz, 1H), 3.63-3.57 (m, 1H), 2.90 (s, 3H), 1.32 (d, J=6.4 Hz, 3H),1.19-1.13 (m, 1H), 0.55-0.48 (m, 2H), 0.41-0.32 (m, 2H). LC-MS m/z:340.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.51 min.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.22 mmol) and phenylboronic acid afforded the title compound(30 mg, 57%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H),8.27 (dd, J=7.6 Hz, 2.0 Hz, 1H), 8.22 (d, J=8.0 Hz, 1H), 7.91 (s, 1H),7.65-7.61 (m, 3H), 3.66-3.61 (m, 1H), 2.86 (s, 3H), 1.29 (d, J=6.4 Hz,3H), 1.12-1.07 (m, 1H), 0.54-0.47 (m, 2H), 0.40-0.33 (m, 2H). LC-MS m/z:321.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.66 min.

(S)—N-(1-Cyclopropylethyl)-5-(3-fluoro-5-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(61 mg, 0.36 mmol) and 3-fluoro-5-methoxyphenylboronic acid afforded thetitle compound (80 mg, 60%) as a white solid. 1H NMR (500 MHz, MeOD-d₄):δ 8.58 (s, 1H), 7.70 (s, 1H), 7.62 (s, 1H), 7.57 (d, J=10.0 Hz, 1H),6.94 (dd, J=11.0 Hz, 2.5 Hz, 1H), 3.93 (s, 3H), 3.73-3.68 (m, 1H), 2.92(s, 3H), 1.40 (d, J=6.5 Hz, 3H), 1.12-1.08 (m, 1H), 0.66-0.58 (m, 2H),0.50-0.47 (m, 1H), 0.40-0.37 (m, 1H). LC-MS m/z: 369.1 [M+H]⁺. HPLCPurity (214 nm): 99%; t_(R)=8.62 min.

(S)—N-(1-Cyclopropylethyl)-5-(3-fluoro-2-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(78 mg, 0.28 mmol) and 3-fluoro-2-methoxyphenylboronic acid afforded thetitle compound (55 mg, 54%) as a grey solid. 1H NMR (500 MHz, DMSO-d₆):δ 8.61 (s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.63 (s,1H), 7.52 (ddd, J=8.0 Hz, 3.0 Hz, 1.0 Hz, 1H), 7.37-7.32 (m, 1H), 3.91(d, J=1.5 Hz, 3H), 3.62-3.58 (m, 1H), 2.86 (s, 3H), 1.24 (d, J=6.5 Hz,3H), 1.00-0.98 (m, 1H), 0.48-0.38 (m, 2H), 0.37-0.31 (m, 1H), 0.30-0.24(m, 1H). LC-MS m/z: 369.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.88 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3-fluoro-2-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(72 mg, 0.22 mmol) and 3-fluoro-2-methoxyphenylboronic acid afforded thetitle compound (55 mg, 59%) as a white solid. 1H NMR (500 MHz, DMSO-d₆)δ 8.70 (s, 1H), 8.47 (d, J=10.0 Hz, 1H), 7.67 (s, 1H), 7.66 (d, J=10.0Hz, 1H), 7.52 (ddd, J=11.5 Hz, 8.0 Hz, 1.0 Hz, 1H), 7.36-7.31 (m, 1H),4.48-4.41 (m, 1H), 3.90 (d, J=1.0 Hz, 3H), 2.88 (s, 3H), 1.22-1.18 (m,1H), 0.68-0.65 (m, 1H), 0.58-0.54 (m, 2H), 0.37-0.34 (m, 1H). LC-MS m/z:423.0 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=9.32 min.

5-(3-Fluoro-2-methoxyphenyl)-7-methy-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (1.5 g, 7.1mmol) and 1,1,1-trifluoropropan-2-amine hydrochloride afforded5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(1.5 g, 69%) as a yellow green solid. LC-MS m/z: 307.1/309.0 [M+H]⁺.t_(R)=1.74 min.

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and 3-fluoro-2-methoxyphenylboronic acid afforded thetitle compound (38 mg, 49%) as a white solid. 1H NMR (500 MHz, CDCl₃): δ8.71 (s, 1H), 8.50 (d, J=9.5 Hz, 1H), 7.65 (d, J=7.5 Hz, 1H), 7.52 (s,1H), 7.31-7.27 (m, 1H), 7.22-7.18 (m, 1H), 5.04-4.95 (m, 1H), 3.96 (d,J=2.0 Hz, 3H), 2.90 (s, 3H), 1.44 (d, J=7.0 Hz, 1H). LC-MS m/z: 397.0[M+H]⁺. HPLC Purity (214 nm): 99%; t_(R)=8.97 min.

5-(3-Cyano-2-methoxyphenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 3-bromo-2-methoxybenzonitrile (2.12 g, 10 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (3.04 g, 12mmol), KOAc (2.44 g, 25 mmol), PdCl₂(dppf).CH₂Cl₂ (860 mg, 1 mmol) wasflushed with N₂ (×3). Then 1,4-dioxane (20 mL) was added and thereaction mixture was stirred at 90° C. for 1 h, filtered andconcentrated in vacuo. The residue was dissolved in isopropyl ether (60mL), filtered and concentrated in vacuo again to afford crude2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (2g) as a black oil.

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileafforded the title compound (20 mg, 26%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.43 (d, J=9.5 Hz, 1H), 8.14 (d, J=6.5 Hz,1H), 8.05 (d, J=8.0 Hz, 1H), 7.72 (s, 1H), 7.54 (t, J=8.0 Hz, 1H),4.43-4.41 (m, 1H), 3.88 (s, 3H), 2.88 (s, 3H), 1.22-1.20 (m, 1H),0.66-0.64 (m, 1H), 0.58-0.54 (m, 2H), 0.36-0.34 (m, 1H). LC-MS m/z:430.1 [M+H]⁺. HPLC: Purity (214 nm): 98.5%; t_(R)=8.65 min.

5-(3-Cyano-2-methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.20 mmol) and2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileafforded the title compound (55 mg, 69%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.37 (d, J=9.5 Hz, 1H), 8.17 (dd, J=8.0Hz, 2.0 Hz, 1H), 8.04 (dd, J=7.5 Hz, 2.0 Hz, 1H), 7.72 (s, 1H), 7.54 (t,J=8.0 Hz, 1H), 4.96-4.91 (m, 1H), 3.87 (s, 3H), 2.88 (s, 3H), 1.39 (d,J=7.0 Hz, 3H). LC-MS m/z: 404.1 [M+H]⁺. HPLC: Purity (214 nm): 98.5%;t_(R)=8.30 min.

(S)-5-(3-Cyano-2-methoxyphenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.22 mmol) and2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileafforded the title compound (8 mg, 10%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.63 (s, 1H), 8.21 (dd, J=7.5 Hz, 1.5 Hz, 1H), 8.04 (dd,J=7.5 Hz, 1.5 Hz, 2H), 7.68 (s, 1H), 7.55 (t, J=7.5 Hz, 1H), 3.88 (s,3H), 3.60-3.58 (m, 1H), 2.87 (s, 3H), 1.23 (d, J=6.5 Hz, 3H), 1.02-0.99(m, 1H), 0.46-0.27 (m, 4H). LC-MS m/z: 376.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.14 min.

(R)-5-(3-Cyano-2-methoxyphenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(140 mg, 0.50 mmol) and2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileafforded the title compound (22 mg, 12%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.62 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.03 (d, J=7.5Hz, 2H), 7.67 (s, 1H), 7.55 (d, J=8.5 Hz, 1H), 3.89 (s, 3H), 3.63-3.59(m, 1H), 2.87 (s, 3H), 1.24 (d, J=6.5 Hz, 3H), 1.04-1.01 (m, 1H),0.48-0.40 (m, 2H), 0.36-0.26 (m, 2H). LC-MS m/z: 376.1 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=8.29 min.

(S)—N-(1-Cyclopropylethyl)-5-(4-fluoro-3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(78 mg, 0.28 mmol) and 4-fluoro-3-methoxyphenylboronic acid afforded thetitle compound (50 mg, 48%) as a grey solid. 1H NMR (400 MHz, DMSO-d₆):δ 8.55 (s, 1H), 8.08 (d, J=7.6 Hz, 1H), 8.00 (dd, J=8.4 Hz, 2.0 Hz, 1H),7.94 (s, 1H), 7.87 (ddd, J=8.4 Hz, 4.4 Hz, 2.0 Hz, 1H), 7.42 (dd, J=11.2Hz, 8.8 Hz, 1H), 3.99 (s, 3H), 3.62-3.58 (m, 1H), 2.84 (s, 3H), 1.29 (d,J=6.4 Hz, 3H), 1.11-1.00 (m, 1H), 0.51-0.40 (m, 2H), 0.40-0.30 (m, 1H),0.30-0.21 (m, 1H). LC-MS m/z: 369.1 [M+H]⁺. HPLC Purity (214 nm): 99%;t_(R)=8.62 min.

(S)—N-(1-Cyclopropylethyl)-5-(4-fluoro-2-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.18 mmol) and 4-fluoro-2-methoxyphenylboronic acid afforded thetitle compound (8 mg, 16%) as a yellow solid. 1H NMR (500 MHz, DMSO-d₆):δ 8.55 (s, 1H), 8.12 (d, J=7.5 Hz, 1H), 7.95 (dd, J=8.0 Hz, 6.0 Hz, 1H),7.67 (s, 1H), 7.20 (dd, J=11.5 Hz, 7.5 Hz, 1H), 7.05 (td, J=8.5 Hz, 2.0Hz, 1H), 3.95 (s, 3H), 3.65-3.58 (m, 1H), 2.83 (s, 3H), 1.24 (d, J=6.5Hz, 3H), 1.02-0.98 (m, 1H), 0.49-0.41 (m, 2H), 0.37-0.30 (m, 1H),0.30-0.21 (m, 1H). LC-MS m/z: 369.1 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=8.81 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4-fluoro-3-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.21 mmol) and 4-fluoro-3-methoxyphenylboronic acid afforded thetitle compound (55.5 mg, 62%) as a white solid. 1H NMR (400 MHz,DMSO-d₆): δ 8.66 (s, 1H), 8.51 (d, J=9.2 Hz, 1H), 8.00 (s, 1H), 7.98(dd, J=8.0 Hz, 1.6 Hz, 1H), 7.85 (ddd, J=8.4 Hz, 4.0 Hz, 2.0 Hz, 1H),7.50 (dd, J=11.2 Hz, 8.8 Hz, 1H), 4.51-4.44 (m, 1H), 3.98 (s, 3H), 2.87(s, 3H), 1.30-1.26 (m, 1H), 0.71-0.67 (m, 1H), 0.60-0.56 (m, 2H),0.40-0.36 (m, 1H). LC-MS m/z: 423.2 [M+H]⁺. HPLC Purity (254 nm): >99%;t_(R)=9.14 min.

5-(4-Fluoro-3-methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and 4-fluoro-3-methoxyphenylboronic acid afforded thetitle compound (38 mg, 49%) as a white solid. 1H NMR (500 MHz, MeOD-d₄):δ 8.63 (s, 1H), 7.97 (dd, J=8.0 Hz, 2.5 Hz, 1H), 7.81 (ddd, J=8.5 Hz,4.0 Hz, 2.0 Hz, 1H), 7.76 (s, 1H), 7.33 (dd, J=10.5 Hz, 8.5 Hz, 1H),5.05-4.98 (m, 1H), 4.04 (s, 3H), 2.94 (s, 3H), 1.53 (d, J=6.5 Hz, 2H).LC-MS m/z: 397.1 [M+H]⁺. HPLC Purity (214 nm): 96%; t_(R)=8.75 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4-fluoro-2-methoxyphenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 4-fluoro-2-methoxyphenylboronic acid afforded thetitle compound (44 mg, 30%) as a white solid. 1H NMR (400 MHz, DMSO-d₆):δ 8.65 (s, 1H), 8.51 (d, J=9.6 Hz, 1H), 7.88 (dd, J=8.4 Hz, 7.2 Hz, 1H),7.70 (s, 1H), 7.21 (dd, J=11.2 Hz, 2.0 Hz, 1H), 7.04 (td, J=8.4 Hz, 2.4Hz, 1H), 4.49-4.43 (m, 1H), 3.94 (s, 3H), 2.84 (s, 3H), 1.24-1.16 (m,1H), 0.67-0.62 (m, 1H), 0.58-0.51 (m, 2H), 0.38-0.32 (m, 1H). LC-MS m/z:423.1 [M+H]⁺. HPLC Purity (254 nm): >99%; t_(R)=9.32 min.

5-(4-Fluoro-2-methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and 4-fluoro-2-methoxyphenylboronic acid afforded thetitle compound (50 mg, 48%) as a yellow solid. 1H NMR (500 MHz,DMSO-d₆): δ 8.65 (s, 1H), 8.46 (d, J=9.5 Hz, 1H), 7.89 (dd, J=8.5 Hz,7.5 Hz, 1H), 7.70 (s, 1H), 7.21 (dd, J=11.5 Hz, 2.0 Hz, 1H), 7.04 (td,J=8.0 Hz, 2.0 Hz 1H), 4.98-4.92 (m, 1H), 3.94 (s, 3H), 2.84 (s, 3H),1.39 (d, J=6.5 Hz, 3H). LC-MS m/z: 397.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.91 min.

5-(2-Cyano-4-fluorophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(40 mg, 0.12 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (28 mg, 55%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.74 (s, 1H), 8.27 (d, J=9.0 Hz, 1H), 8.22-8.19 (m, 2H), 7.89 (td,J=8.5 Hz, 3.0 Hz, 1H), 7.83 (s, 1H), 4.30-4.25 (m, 1H), 2.89 (s, 3H),1.37-1.33 (m, 1H), 0.71-0.68 (m, 1H), 0.64-0.61 (m, 1H), 0.52-0.49 (m,1H), 0.34-0.31 (m, 1H). LC-MS m/z: 418.1 [M+H]⁺. HPLC: Purity (214 nm):98%; t_(R)=8.63 min.

5-(2-Carbamoyl-4-fluorophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol), 2-cyano-4-fluorophenylboronic acid and Na₂CO₃ (0.3mmol) afforded the title compound (44 mg, 68%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.25 (d, J=9.2 Hz, 1H), 8.06 (s, 1H),7.83 (dd, J=8.8 Hz, 5.2 Hz, 1H), 7.55-7.46 (m, 3H), 7.40 (s, 1H),4.27-4.20 (m, 1H), 2.85 (s, 3H), 1.42-1.37 (m, 1H), 0.67-0.58 (m, 3H),0.30-0.25 (m, 1H). LC-MS m/z: 436.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.80 min.

(S)-5-(2-Cyano-4-fluorophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(300 mg, 1.079 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (350 mg, 90%) as a yellow solid. 1H NMR (500 MHz,DMSO-d₆): δ 8.65 (s, 1H), 8.23 (dd, J=8.5 Hz, 5.5 Hz, 1H), 8.19 (dd,J=8.5 Hz, 2.5 Hz, 1H), 7.94 (s, 1H), 8.00 (d, J=8.5 Hz, 1H), 7.88 (td,J=9.0 Hz, 3.0 Hz, 1H), 7.78 (s, 1H), 3.58-3.51 (m, 1H), 2.88 (s, 3H),1.28 (d, J=6.5 Hz, 3H), 1.11-1.06 (m, 1H), 0.48-0.42 (m, 1H), 0.40-0.30(m, 2H), 0.27-0.22 (m, 1H). LC-MS m/z: 364.1 [M+H]⁺. HPLC Purity (214nm): >99%; t_(R)=8.14 min.

(R)-5-(2-Cyano-4-fluorophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.36 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (54 mg, 42%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ8.76 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.92 (dd, J=8.5 Hz, 4.5 Hz, 1H),7.62 (dd, J=8.0 Hz, 2.5 Hz, 1H), 7.49 (td, J=8.5 Hz, 2.5 Hz, 1H), 7.19(s, 1H), 3.72-3.68 (m, 1H), 2.94 (s, 3H), 1.35 (d, J=6.5 Hz, 3H),1.10-1.07 (m, 1H), 0.53-0.49 (m, 1H), 0.47-0.42 (m, 2H), 0.30-0.28 (m,1H). LC-MS m/z: 364.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.21min.

(R)-5-(2-Cyan-4-fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (40 mg, 38%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): 8.75 (s, 1H), 8.23-8.20 (m, 2H), 8.12 (d, J=9.5 Hz, 1H), 7.89(td, J=8.5 Hz, 2.0 Hz, 1H), 7.82 (s, 1H), 5.03-4.97 (m, 1H), 2.89 (s,3H), 1.43 (d, J=7.0 Hz, 3H). LC-MS m/z: 392.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.37 min.

(S)-5-(2-Cyano-4-fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 2-cyano-4-fluorophenylboronic acid afforded thetitle compound (42 mg, 42%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): 8.75 (s, 1H), 8.23-8.20 (m, 2H), 8.12 (d, J=9.5 Hz, 1H), 7.89(td, J=8.5 Hz, 2.0 Hz, 1H), 7.82 (s, 1H), 5.03-4.97 (m, 1H), 2.89 (s,3H), 1.43 (d, J=7.0 Hz, 3H). LC-MS m/z: 392.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.38 min.

(S)-5-(3-Cyano-4-fluorophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.25 mmol) and 3-cyano-4-fluorophenylboronic acid afforded thetitle compound (47 mg, 40%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ 8.84 (dd, J=6.0 Hz, 2.0 Hz, 1H), 8.68-8.64 (m, 1H), 8.61 (s, 1H), 8.09(d, J=7.6 Hz, 1H), 8.02 (s, 1H), 7.82 (t, J=9.2 Hz, 1H), 3.62-3.58 (m,1H), 2.86 (s, 3H), 1.29 (d, J=6.4 Hz, 3H), 1.16-1.10 (m, 1H), 0.55-0.48(m, 2H), 0.41-0.32 (m, 2H). LC-MS m/z: 364.2 [M+H]⁺. HPLC Purity (214nm): >99%; t_(R)=8.31 min.

5-(3-Cyano-4-fluorophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 3-cyano-4-fluorophenylboronic acid afforded thetitle compound (36 mg, 47%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆):δ 8.77 (dd, J=6.5 Hz, 2.0 Hz, 1H), 8.70 (s, 1H), 8.63-8.59 (m, 1H), 8.48(d, J=9.5 Hz, 1H), 8.05 (s, 1H), 7.86 (d, J=9.5 Hz, 1H), 4.46-4.41 (m,1H), 2.87 (s, 3H), 1.36-1.31 (m, 1H), 0.71-0.67 (m, 1H), 0.62-0.56 (m,2H), 0.42-0.38 (m, 1H). LC-MS m/z: 418.1 [M+H]⁺. HPLC Purity (214nm): >99%; t_(R)=8.74 min.

5-(3-Cyano-4-fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.20 mmol) and 3-cyano-4-fluorophenylboronic acid afforded thetitle compound (8 mg, 11%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆):δ 8.79 (dd, J=6.0 Hz, 2.4 Hz, 1H), 8.71 (s, 1H), 8.65-8.60 (m 1H), 8.41(d, J=9.2 Hz, 1H), 8.06 (s, 1H), 7.86 (t, J=8.0 Hz, 1H), 5.00-4.94 (m,1H), 2.87 (s, 3H), 1.46 (d, J=6.8 Hz, 3H). LC-MS m/z: 392.0 [M+H]⁺.HPLC: Purity (214 nm): 97%; t_(R)=8.37 min.

(S)-5-(3-Carbamoyl-4-fluorophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(110 mg, 0.35 mmol) and 3-carbamoyl-4-fluorophenylboronic acid affordedthe title compound (75 mg, 55%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.62 (d, J=6.0 Hz, 1H), 8.57 (s, 1H), 8.41 (brs, 1H), 8.21(d, J=7.5 Hz, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.84 (s, 1H), 7.57 (t,J=9.0 Hz, 1H), 3.60-3.56 (m, 1H), 2.86 (s, 3H), 1.30 (d, J=6.0 Hz, 3H),1.13-1.10 (m, 1H), 0.53-0.50 (m, 2H), 0.35-0.32 (m, 2H). LC-MS m/z:382.1 [M+H]⁺. HPLC Purity (214 nm): 99%; t_(R)=6.69 min.

5-(6-Carbamoylpyridin-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a mixture of5-(6-cyanopyridin-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(38 mg, 0.095 mmol) in DMSO (2 mL) was added K₂CO₃ (2 mg, 0.014 mmol)and H₂O₂(4 mg, 0.014 mmol) at 25° C. and the mixture was stirred for 15h, and purified by preparative HPLC (10 mM NH₄HCO₃/MeCN) to afford thetitle compound (7.0 mg, 18%) as a pale yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.78 (s, 1H), 8.72 (s, 1H), 8.66 (s, 1H), 8.57 (d, J=8.0 Hz,1H), 8.53 (d, J=9.5 Hz, 1H), 8.29 (t, J=7.5 Hz, 1H), 8.23 (d, J=7.5 Hz,1H), 7.95 (s, 1H), 4.45-4.41 (m, 1H), 2.93 (s, 3H), 1.42-1.38 (m, 1H),0.74-0.70 (m, 1H), 0.66-0.60 (m, 2H), 0.43-0.39 (m, 1H). LC-MS m/z:419.0 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.40 min.

5-(3-Carbamoyl-4-fluorophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 3-carbamoyl-4-fluorophenylboronic acid affordedthe title compound (27.4 mg, 35%) as a white solid. 1H NMR (500 MHz,DMSO-d₆) δ 8.67 (s, 1H), 8.60-8.58 (m, 2H), 8.40-8.37 (m, 1H), 8.03 (s,1H), 7.90 (s, 1H), 7.84 (s, 1H), 7.58 (t, J=9.0 Hz, 1H), 4.40-4.36 (m,1H), 2.87 (s, 3H), 1.37-1.34 (m, 1H), 0.71-0.66 (m, 1H), 0.62-0.60 (m,2H), 0.39-0.36 (m, 1H). LC-MS m/z: 436.0 [M+H]⁺. HPLC: Purity (214 nm):97.8%; t_(R)=7.33 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.11 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (14 mg, 31%) as a yellowsolid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.56 (d, J=9.5 Hz, 1H),8.30 (dd, J=8.5 Hz, 5.0 Hz, 1H), 7.95 (s, 1H), 7.50 (t, J=9.0 Hz, 1H),4.48-4.42 (m, 1H), 2.51 (s, 3H), 1.34-1.27 (m, 1H), 0.71-0.64 (m, 1H),0.61-0.55 (m, 2H), 0.41-0.36 (m, 1H). LC-MS m/z: 393.0 [M+H]⁺. HPLC:Purity (214 nm): 99%; t_(R)=9.19 min.

5-(4-Fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(4-fluorophenyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.11 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (14 mg, 33%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.46 (d, J=9.5 Hz, 1H), 8.30 (dd, J=9.0Hz, 6.0 Hz, 1H), 7.95 (s, 1H), 7.50 (t, J=9.0 Hz, 1H), 5.00-4.94 (m,1H), 2.86 (s, 3H), 1.46 (d, J=6.5 Hz, 1H). LC-MS m/z: 367.1 [M+H]⁺.HPLC: Purity (214 nm): 99%; t_(R)=8.86 min.

5-(Cyclopropylamino)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.13 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (24 mg, 57%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.64 (d, J=9.0 Hz, 1H), 8.28 (s, 1H), 8.19 (s, 1H), 6.22(s, 1H), 4.90-4.84 (m, 1H), 2.70-2.66 (m, 1H), 2.56 (s, 3H), 1.36 (d,J=7.0 Hz, 3H), 0.80-0.76 (m, 2H), 0.56-0.52 (m, 2H). LC-MS m/z: 328.1[M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.44 min.

(S)-5-(Cyclopropylamino)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(cyclopropylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(30 mg, 0.13 mmol) and (S)-1-cyclopropylethanamine afforded the titlecompound (13 mg, 31%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.00 (s, 1H), 7.93 (s, 1H), 7.90 (s, 1H), 5.98 (s, 1H), 3.40-3.34 (m,1H), 2.58-2.51 (m, 1H), 2.34 (s, 3H), 1.01 (d, J=6.5 Hz, 3H), 0.74-0.69(m, 1H), 0.60-0.56 (m, 2H), 0.36-0.31 (m, 2H), 0.25-0.12 (m, 2H),0.12-0.08 (m, 1H), 0.00-0.05 (m, 1H). LC-MS m/z: 300.2 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=7.18 min.

(R)-5-(Benzo[d]oxazol-5-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (88 mg, 75%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.90 (s, 1H), 8.69 (d, J=2.0 Hz, 1H), 8.66 (s, 1H), 8.53 (d,J=9.0 Hz, 1H), 8.35 (dd, J=8.5 Hz, 1.5 Hz, 1H), 8.08 (s, 1H), 8.04 (d,J=8.5 Hz, 1H), 5.00-4.96 (m, 1H), 2.88 (s, 3H), 1.48 (d, J=7.0 Hz, 3H).LC-MS m/z: 390.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.90 min.

(S)-5-(Benzo[d]oxazol-5-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.32 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (18 mg, 18%) as a white solid. ¹H NMR (500 MHz,MeOD-d₄) δ 8.64 (s, 2H), 8.63 (s, 1H), 8.38 (d, J=8.5 Hz, 1H), 7.92 (d,J=8.5 Hz, 1H), 7.86 (s, 1H), 5.02-5.49 (m, 1H), 2.97 (s, 3H), 1.57 (d,J=7.0 Hz, 3H). LC-MS m/z: 390.1 [M+H]⁺. HPLC: Purity (254 nm): >99%;t_(R)=7.90 min.

5-(3-Chloro-1H-pyrazol-1-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.23 mmol) and 3-chloro-1H-pyrazole afforded the title compound(17 mg, 20%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.72 (d,J=2.0 Hz, 1H), 8.66 (s, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.77 (s, 1H), 6.93(d, J=3.0 Hz, 1H), 4.96-4.92 (m, 1H), 2.87 (s, 3H), 1.46 (d, J=7.0 Hz,3H). LC-MS m/z: 373.0 [M+H]⁺. HPLC: Purity (214 nm): 99%; t_(R)=8.79min.

5-(Benzo[d]oxazol-5-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (45 mg, 36%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.91 (s, 1H), 8.70 (s, 1H), 8.67 (s, 1H), 8.62 (d, J=9.0 Hz,1H), 8.36 (d, J=9.0 Hz, 1H), 8.10 (s, 1H), 8.05 (d, J=8.0 Hz, 1H),4.53-4.48 (m, 1H), 2.88 (s, 3H), 1.32-1.28 (m, 1H), 0.73-0.69 (m, 1H),0.62-0.57 (m, 2H), 0.43-0.40 (m, 1H). LC-MS m/z: 416.1 [M+H]⁺. HPLCPurity (214 nm): 98%; t_(R)=9.09 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3-fluoro-1H-pyrazol-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) in anhydrous THF (3 mL) was added3-fluoro-1H-pyrazole (25 mg, 0.288 mmol) and K₂CO₃ (100 mg, 0.72 mmol).The mixture was stirred at 70° C. for 8 h, poured into H₂O (20 mL) andextracted with EA (20 mL×2). The organic layers were dried overanhydrous Na₂SO₄, and filtered. The filtrate was concentrated in vacuoand the residue was purified by preparative TLC (PE/EA=2/1) to affordthe title compound (30 mg, 33%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.65 (s, 1H), 8.62 (t, J=3.0 Hz, 1H), 8.14 (d, J=9.5 Hz, 1H),7.67 (s, 1H), 6.67 (q, J=3.0 Hz, 1H), 4.33-4.27 (m, 1H), 2.86 (s, 3H),1.47-1.23 (m, 1H), 0.73-0.56 (m, 3H), 0.39-0.36 (m, 1H). LC-MS m/z:383.1 [M+H]⁺. HPLC Purity (214 nm): 96.46%; t_(R)=8.82 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3-fluoro-1H-pyrazol-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.21 mmol), 3-fluoro-1H-pyrazole (18 mg, 0.21 mmol), and K₂CO₃(58 mg, 0.42 mmol) in DMF (2 mL) was stirred at 60° C. for 2 h, pouredinto H₂O (10 mL), and extracted with EA (30 mL×3). The combined organicphases were washed with H₂O (50 mL) and brine (50 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo,and the residue was purified by silica gel column chromatography(PE/EA=2/1) and preparative HPLC (10 mM NH₄HCO₃/MeCN) to afford thetitle compound (14 mg, 24%) as a white solid. ¹H NMR (400 MHz, MeOD-d₄):δ 8.59 (s, 1H), 8.55 (t, J=2.4 Hz, 1H), 7.65 (s, 1H), 7.44 (q, J=2.8 Hz,1H), 4.36-4.30 (m, 1H), 2.92 (s, 3H), 1.40-1.34 (m, 1H), 0.82-0.75 (m,1H), 0.70-0.58 (m, 2H), 0.52-0.46 (m, 1H). LC-MS m/z: 383.1 [M+H]⁺.HPLC: Purity (214 nm): 93%; t_(R)=8.83 min.

N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(6-(pyrimidin-2-yl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F, 2,6-dibromopyridine (2.0 g, 8.44 mmol)and 2-(tributylstannyl)pyrimidine afforded2-(6-bromopyridin-2-yl)pyrimidine (600 mg, 40%) as a yellow solid. LC-MSm/z: 237.1 [M+H]⁺. LC-MS Purity (214 nm): >89%; t_(R)=1.45 min.

Following general procedure E*, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (200 mg, 0.83mmol) and 2-(6-bromopyridin-2-yl)pyrimidine afforded ethyl7-methyl-5-(6-(pyrimidin-2-yl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(68 mg, 22%) as a yellow solid. LC-MS m/z: 361.1 [M+H]⁺. LC-MS Purity(214 nm): >96%; t_(R)=1.67 min.

Following general procedure B*, ethyl7-methyl-5-(6-(pyrimidin-2-yl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(60 mg, 0.16 mmol) afforded7-methyl-5-(6-(pyrimidin-2-yl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (43 mg, 83%) as a yellow solid. LC-MS m/z: 333.1 [M+H]⁺. LC-MSPurity (214 nm): >83%; t_(R)=1.13 min.

Following general procedure A,7-methyl-5-(6-(pyrimidin-2-yl)pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (40 mg, 0.12 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (10 mg, 18%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆): δ 9.08 (d, J=5.2 Hz, 1H), 8.74 (s,1H), 8.60-8.54 (m, 3H), 8.32 (d, J=7.6 Hz, 1H), 8.26 (s, 1H), 7.66 (t,J=4.8 Hz, 1H), 4.48-4.41 (m, 1H), 2.96 (s, 3H), 1.45-1.37 (m, 1H),0.75-0.70 (m, 1H), 0.66-0.60 (m, 2H), 0.46-0.40 (m, 1H). LC-MS m/z:454.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.23 min.

5-(3-(1,2,4-Oxadiazol-3-yl)phenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of hydroxylamine hydrochloride (1.15 g, 16.5 mmol) andNa₂CO₃ (1.0 g, 9.9 mmol) in 16 mL of H₂O and 8 mL EtOH was added3-bromobenzonitrile (1.2 g, 6.6 mmol). The reaction mixture was refluxedfor 6 h, and extracted with EA (3×40 mL). The combined organic layerswere washed with brine (100 mL), dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo to afford3-bromo-N-hydroxybenzimidamide (800 mg, 56%) as a white solid. LC-MSm/z: 215.0 [M+H]⁺.

To a solution of 3-bromo-N-hydroxybenzimidamide (1.5 g, 7.0 mmol) intriethoxymethane (5.0 mL) was added p-TsOH.H₂O (133 mg, 0.7 mmol). Thereaction mixture was stirred at 90° C. for 16 h, and concentrated invacuo. The residue was purified by flash chromatography to afford3-(3-bromophenyl)-1,2,4-oxadiazole as a white solid (900 mg, 57%). LC-MSm/z: 225.1 [M+H]⁺.

Following general procedure D, 3-(3-bromophenyl)-1,2,4-oxadiazole (100mg, 0.45 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) afforded3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-oxadiazolewhich was used in the next step without further purification. LC-MS m/z:273.1 [M+H]⁺.

Following general procedure D, 3-(3-bromophenyl)-1,2,4-oxadiazole (100mg, 0.45 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) afforded3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-oxadiazolewhich was used in the next step without further purification. LC-MS m/z:273.1 [M+H]⁺.

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(66 mg, 0.19 mmol) and3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,2,4-oxadiazoleafforded the title compound (10 mg, 20%) as a white solid. ¹H NMR (500MHz, CDCl₃): δ 8.88 (s, 1H), 8.82 (s, 1H), 8.72 (s, 1H), 8.64 (d, J=9.0Hz, 1H), 8.33 (d, J=7.5 Hz, 1H), 8.29 (d, J=7.5 Hz, 1H), 7.73 (t, J=7.5Hz, 1H), 7.44 (s, 1H), 4.45-4.42 (m, 1H), 2.96 (s, 3H), 1.36-1.30 (m,1H), 0.76-0.73 (m, 1H), 0.65-0.52 (m, 3H). LC-MS m/z: 443.1 [M+H]⁺. HPLCPurity (254 nm): 99%; t_(R)=8.80 min.

5-(3-(1,3,5-Triazin-2-yl)phenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(93 mg, 0.28 mmol) and2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,5-triazineafforded the title compound (64.5 mg, 51%) as a grey solid. ¹H NMR (500MHz, DMSO-d₆) δ 9.39 (s, 3H), 8.70 (s, 1H), 8.68 (d, J=10.0 Hz, 1H),8.66 (d, J=8.0 Hz, 1H), 8.53 (d, J=8.0 Hz, 1H), 8.07 (s, 1H), 7.87 (t,J=8.0 Hz, 1H), 4.46-4.37 (m, 1H), 2.91 (s, 3H), 1.49-1.43 (m, 1H),0.82-0.76 (m, 1H), 0.70-0.61 (m, 2H), 0.46-0.40 (m, 1H). LC-MS m/z:454.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.85 min.

5-(Isothiazol-5-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(35 mg, 0.13 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (13.5 mg, 28%) as a white solid. ¹H NMR (400MHz, MeOD-d₄) δ 8.67 (d, J=2.0 Hz, 1H), 8.64 (s, 1H), 8.10 (d, J=2.0 Hz,1H), 7.74 (s, 1H), 5.00-4.93 (m, 1H), 2.94 (s, 3H), 1.55 (d, J=7.2 Hz,3H). LC-MS m/z: 356.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=9.69min.

5-(3,3-Difluoropiperidin-1-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and 3,3-difluoropiperidine hydrochloride afforded thetitle compound (67 mg, 66%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.27 (s, 1H), 8.23 (d, J=9.5 Hz, 1H), 7.05 (s, 1H), 4.89-4.85 (m, 1H),4.13 (t, J=12.5 Hz, 2H), 3.80 (brs, 2H), 2.63 (s, 3H), 2.20-2.12 (m,2H), 1.78 (brs, 2H), 1.36 (d, J=7.0 Hz, 3H). LC-MS m/z: 392.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=7.94 min.

5-(3,3-Difluoropyrrolidin-1-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and 3,3-difluoropyrrolidine hydrochloride affordedthe title compound (68 mg, 68%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.27 (s, 2H), 6.64 (brs, 1H), 4.89-4.84 (m, 1H), 4.08-4.00(m, 2H), 3.85-3.80 (m, 2H), 2.65 (s, 3H), 2.66-2.64 (m, 2H), 1.38 (d,J=7.0 Hz, 3H). LC-MS m/z: 378.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=7.91 min.

5-(4,4-Difluoropiperidin-1-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure G,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and 4,4-difluoropiperidine hydrochloride afforded thetitle compound (60 mg, 59%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.27 (s, 1H), 8.22 (d, J=9.5 Hz, 1H), 7.03 (s, 1H), 4.89-4.84 (m, 1H),3.86 (brs, 4H), 2.63 (s, 3H), 2.13-2.06 (m, 4H), 1.37 (d, J=7.0 Hz, 3H).LC-MS m/z: 392.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.14 min.

(S)-5-(Benzo[d][1,3]dioxol-4-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.28 mmol) and benzo[d][1,3]dioxol-4-ylboronic acid afforded thetitle compound (77 mg, 77%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.57 (s, 1H), 8.21 (d, J=8.0 Hz, 1H), 7.80 (s, 1H), 7.72 (d, J=8.0 Hz,1H), 7.15 (d, J=7.0 Hz, 1H), 7.09 (t, J=8.0 Hz, 1H), 6.26 (s, 1H), 6.25(s, 1H), 3.65-3.61 (m, 1H), 2.85 (s, 3H), 1.28 (d, J=6.5 Hz, 3H),1.05-1.01 (m, 1H), 0.54-0.42 (m, 2H), 0.38-0.26 (m, 2H). LC-MS m/z:365.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.58 min.

5-(Benzo[d][1,3]dioxol-4-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and benzo[d][1,3]dioxol-4-ylboronic acid afforded thetitle compound (29 mg, 39%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.66 (s, 1H), 8.64 (d, J=10.0 Hz, 1H), 7.86 (s, 1H), 7.67 (d, J=8.5Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 7.08 (t, J=8.0 Hz, 1H), 6.26 (s, 1H),6.20 (s, 1H), 4.47-4.42 (m, 1H), 2.87 (s, 3H), 1.25-1.22 (m, 1H),0.72-0.68 (m, 1H), 0.60-0.56 (m, 2H), 0.38-0.35 (m, 1H). LC-MS m/z:419.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=9.08 min.

5,7-Dimethyl-N-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.52mmol) and 2,2,2-trifluoro-1-(4-fluorophenyl)ethanamine afforded thetitle compound (36 mg, 38%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄)δ 8.54 (s, 1H), 7.64 (dd, J=8.5 Hz, 5.5 Hz, 2H), 7.23 (t, J=8.5 Hz, 2H),7.08 (s, 1H), 5.99 (q, J=8.0 Hz, 1H), 2.81 (s, 3H), 2.76 (s, 3H). LC-MSm/z: 367.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=9.77 min.

5-(5-Cyanofuran-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 5-bromofuran-2-carbonitrile afforded the titlecompound (3 mg, 3%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.71(s, 1H), 8.43 (d, J=9.5 Hz, 1H), 7.90 (d, J=4.0 Hz, 1H), 7.84 (s, 1H),7.68 (d, J=4.0 Hz, 1H), 4.55-4.48 (m, 1H), 2.86 (s, 3H), 1.36-1.29 (m,1H), 0.70-0.64 (m, 1H), 0.62-0.52 (m, 2H), 0.51-0.45 (m, 1H). LC-MS m/z:390.0 [M+H]⁺. HPLC Purity (214 nm): 97%; t_(R)=9.17 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(furan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and tributyl(furan-2-yl)stannane afforded the titlecompound (23 mg, 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ8.61 (s, 1H), 8.52 (d, J=9.6 Hz, 1H), 8.10 (d, J=1.6 Hz, 1H), 7.67 (s,1H), 7.49 (d, J=3.2 Hz, 1H), 6.85 (dd, J=3.2 Hz, 1.6 Hz, 1H), 4.54-4.45(m, 1H), 2.83 (s, 3H), 1.34-1.26 (m, 1H), 0.70-0.44 (m, 4H). LC-MS m/z:365.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.73 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(furan-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and furan-3-ylboronic acid afforded the titlecompound (75 mg, 79%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ8.54 (s, 1H), 8.44 (s, 1H), 7.74 (t, J=1.6 Hz, 1H), 7.48 (s, 1H), 7.06(d, J=1.6 Hz, 1H), 4.46-4.42 (m, 1H), 2.86 (s, 3H), 1.33-1.31 (m, 1H),0.78-0.76 (m, 1H), 0.67-0.64 (m, 1H), 0.57-0.52 (m, 2H). LC-MS m/z:365.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=10.32 min.

5-(4-Cyanothiophen-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 4-bromothiophene-3-carbonitrile afforded thetitle compound (12 mg, 12%) as a white solid. ¹H NMR (400 MHz, MeOD-d₄):δ 8.66 (s, 1H), 8.55 (d, J=3.0 Hz, 1H), 8.53 (d, J=3.0 Hz, 1H), 7.68 (s,1H), 4.16-4.12 (m, 1H), 2.94 (s, 3H), 1.68-1.65 (m, 1H), 0.80-0.76 (m,1H), 0.63-0.58 (m, 2H), 0.39-0.34 (m, 1H). LC-MS m/z: 406.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.93 min.

5-(3-Cyanothiophen-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.301 mmol) and 2-bromothiophene-3-carbonitrile afforded thetitle compound (2.3 mg, 2%) as a yellow solid. 1H NMR (500 MHz, MeOD-d₄)δ 8.69 (s, 1H), 7.97 (d, J=5.5 Hz, 1H), 7.80 (s, 1H), 7.60 (d, J=5.0 Hz,1H), 4.30-4.26 (m, 1H), 2.97 (s, 1H), 1.53-1.50 (m, 1H), 0.81-0.78 (m,1H), 0.64-0.60 (m, 2H), 0.46-0.44 (m, 1H). LC-MS m/z: 406.0 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=10.13 min.

N-((1R,4R)-4-tert-butoxycyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (50 mg, 0.26mmol) and (1R,4R)-4-tert-butoxycyclohexanamine afforded the titlecompound (22 mg, 38%) as a light brown solid. ¹H NMR (500 MHz, MeOD-d₄):δ 8.48 (s, 1H), 7.01 (s, 1H), 3.90-3.88 (m, 1H), 3.63-3.60 (m, 1H), 2.78(s, 3H), 2.67 (s, 3H), 2.13-2.10 (m, 2H), 1.93-1.91 (m, 2H), 1.52-1.46(m, 4H), 1.24 (s, 9H). LC-MS m/z: 345.2 [M+H]⁺. HPLC: Purity (254nm): >99%; t_(R)=8.55 min.

N-((1R,4R)-4-iso-Butoxycyclohexyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5,7-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (100 mg, 0.52mmol) and (1R,4R)-4-iso-butoxycyclohexanamine afforded the titlecompound (56 mg, 31%) as a light brown solid. ¹H NMR (500 MHz, MeOD-d₄)δ 8.31 (s, 1H), 6.85 (s, 1H), 3.82-3.78 (m, 1H), 3.26-3.20 (m, 1H), 3.15(d, J=6.5 Hz, 2H), 2.64 (s, 3H), 2.53 (s, 3H), 2.02-1.94 (m, 4H),1.72-1.66 (m, 1H), 1.38-1.30 (m, 4H), 0.81 (d, J=6.5 Hz, 6H). LC-MS m/z:345.2 [M+H]⁺. HPLC: Purity (214 nm): 99%; t_(R)=9.65 min.

(S)-5-(Benzo[d]thiazol-5-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and benzo[d]thiazol-5-ylboronic acid afforded thetitle compound (72 mg, 64%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.53 (s, 1H), 8.98 (s, 1H), 8.56 (s, 1H), 8.41 (d, J=8.5 Hz,1H), 8.38 (d, J=8.5 Hz, 1H), 8.26 (d, J=6.0 Hz, 1H), 8.08 (s, 1H),3.68-3.63 (m, 1H), 2.87 (s, 3H), 1.31 (d, J=6.0 Hz, 3H), 1.15-1.11 (m,1H), 0.60-0.51 (m, 2H), 0.44-0.40 (m, 1H), 0.40-0.32 (m, 1H). LC-MS m/z:378.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.08 min.

(R)-5-(Benzo[d]thiazol-5-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and benzo[d]thiazol-5-ylboronic acid afforded thetitle compound (38 mg, 34%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 9.55 (s, 1H), 9.02 (s, 1H), 8.59 (s, 1H), 8.46-8.40 (m, 2H),8.29 (d, J=7.6 Hz, 1H), 8.12 (s, 1H), 3.68-3.61 (m, 1H), 2.89 (s, 3H),1.31 (d, J=6.4 Hz, 1H), 1.17-1.10 (m, 1H), 0.60-0.52 (m, 2H), 0.46-0.32(m, 2H). LC-MS m/z: 378.1 [M+H]⁺. HPLC: Purity (214 nm): 99%; t_(R)=8.07min.

(R)-5-(5-Fluoro-2-methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.23 mmol) and 5-fluoro-2-methoxyphenylboronic acid afforded thetitle compound (36 mg, 39%) as a yellow solid. 1H NMR (500 MHz, DMSO-d₆)δ 8.67 (s, 1H), 8.45 (d, J=9.5 Hz, 1H), 7.79 (d, J=1.0 Hz, 1H), 7.69(dd, J=9.5 Hz, 3.0 Hz, 1H), 7.43 (td, J=9.0 Hz, 3.0 Hz, 1H), 7.30 (dd,J=9.5 Hz, 4.5 Hz, 1H), 4.96-4.90 (m, 1H), 3.92 (s, 3H), 2.86 (s, 3H),1.39 (d, J=7.0 Hz, 3H). LC-MS m/z: 397.1 [M+H]⁺. HPLC Purity (214 nm):99.15%; t_(R)=8.83 min.

(S)-5-(5-Fluoro-2-methoxyphenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.32 mmol) and 5-fluoro-2-methoxyphenylboronic acid affordedthe title compound (18 mg, 14%) as a white solid. 1H NMR (400 MHz,DMSO-d₆) δ 8.68 (s, 1H), 8.46 (d, J=9.2 Hz, 1H), 7.79 (s, 1H), 7.69 (dd,J=9.6 Hz, 3.2 Hz, 1H), 7.44 (td, J=8.0 Hz, 3.2 Hz, 1H), 7.30 (dd, J=8.8Hz, 4.4 Hz, 1H), 4.97-4.91 (m, 1H), 3.92 (s, 3H), 2.85 (s, 3H), 1.40 (d,J=6.4 Hz, 3H). LC-MS m/z: 397.1 [M+H]⁺. HPLC: Purity (254 nm): 98%;t_(R)=8.84 min.

(S)—N-(1-Cyclopropylethyl)-5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(35 mg, 0.13 mmol) and (S)-1-cyclopropylethanamine afforded the titlecompound (18.6 mg, 42%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ8.66 (d, J=2.0 Hz, 1H), 8.60 (s, 1H), 8.24 (d, J=7.6 Hz, 1H), 8.09 (d,J=2.0 Hz, 1H), 7.70 (s, 1H), 3.70-3.65 (m, 1H), 2.93 (s, 3H), 1.41 (d,J=6.4 Hz, 3H), 1.13-1.10 (m, 1H), 0.66-0.58 (m, 2H), 0.49-0.44 (m, 1H),0.39-0.35 (m, 1H). LC-MS m/z: 328.1 [M+H]⁺. HPLC: Purity (214 nm): 99%;t_(R)=9.64 min.

(R)—N-(1-Cyclopropylethyl)-5-(isothiazol-5-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 5-bromoisothiazole (325 mg, 2.0 mmol) in anhydrous THF(10 mL) was added n-BuLi (1.0 mL, 2.5 mmol, 2.5M solution in hexane) at−78° C. under N₂. The mixture was stirred at −78° C. for 0.5 h, followedby the addition of Bu₃SnCl (750 mg, 2.0 mmol) at −78° C., and stirred at−78° C. for another hour before being allowed to warm to RT. Afterconcentration in vacuo, the residue was purified by preparative TLC toafford 5-(tributylstannyl)isothiazole (500 mg) as colourless oil. LC-MSm/z: 276.0 [M+H]⁺, t_(R)=2.87 min.

Following general procedure F,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(55 mg, 0.2 mmol) and 5-(tributylstannyl)isothiazole afforded the titlecompound (4 mg, 12%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ 8.68(d, J=1.2 Hz, 1H), 8.62 (s, 1H), 8.11 (s, 1H), 7.72 (s, 1H), 3.73-3.66(m, 1H), 2.94 (s, 3H), 8.43 (d, J=5.2 Hz, 3H), 1.16-1.12 (m, 1H),0.67-0.58 (m, 2H), 0.51-0.46 (m, 1H), 0.41-0.36 (m, 1H). LC-MS m/z:328.1 [M+H]⁺. HPLC: Purity (254 nm): >99%, t_(R)=7.81 min.

5-(4-Fluoropyridin-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.326 mmol) and 4-fluoropyridin-3-ylboronic acid afforded thetitle compound (32 mg, 27%) as a grey yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.25 (d, J=10.0 Hz, 1H), 8.80 (t, J=7.0 Hz, 1H), 8.74 (s,1H), 8.41 (d, J=9.0 Hz, 1H), 7.82 (s, 1H), 7.64 (dd, J=11.5 Hz, 6.0 Hz,1H), 4.98-4.93 (m, 1H), 2.89 (s, 3H), 1.41 (d, J=7.0 Hz, 1H). LC-MS m/z:368.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.37 min.

(R)-5-(5-Chloropyridin-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.23 mmol) and 5-chloropyridin-3-ylboronic acid afford the titlecompound (22.6 mg, 28%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ9.38 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.5 Hz, 1H), 8.71 (s, 1H), 8.70 (t,J=2.5 Hz, 1H), 8.40 (d, J=9.0 Hz, 1H), 8.10 (s, 1H), 4.99-4.95 (m, 1H),2.88 (s, 3H), 1.45 (d, J=7.0 Hz, 3H). LC-MS m/z: 384.0 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.25 min.

(S)-5-(5-Chloropyridin-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(110 mg, 0.35 mmol) and 5-chloropyridin-3-ylboronic acid afforded thetitle compound (55 mg, 41%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.39 (d, J=1.5 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.73 (s,1H), 8.71 (t, J=2.0 Hz, 1H), 8.40 (d, J=9.5 Hz, 1H), 8.11 (s, 1H),5.00-4.96 (m, 1H), 2.89 (s, 3H), 1.45 (d, J=7.0 Hz, 3H). LC-MS m/z:384.1 [M+H]⁺. HPLC Purity (214 nm): 98%; t_(R)=8.25 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3-fluoropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 2-bromo-3-fluoropyridine afforded the titlecompound (5.2 mg, 6%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.72(s, 1H), 8.69 (d, J=2.5 Hz, 1H), 8.64 (d, J=9.5 Hz, 1H), 8.09 (s, 1H),8.04 (dd, J=12.5 Hz, 9.0 Hz, 1H), 7.76-7.73 (m, 1H), 4.42 (m, 1H), 2.91(s, 3H), 1.23-1.19 (m, 1H), 0.72-0.68 (m, 1H), 0.59-0.57 (m, 2H),0.39-0.37 (m, 1H). LC-MS m/z: 394.1 [M+H]⁺. HPLC: Purity (214 nm): 99%;t_(R)=8.61 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-fluoropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol), and 2-bromo-5-fluoropyridine afforded the titlecompound (14 mg, 15%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.83 (d, J=2.5 Hz, 1H), 8.71 (s, 1H), 8.50 (d, J=10.5 Hz, 1H), 8.49-8.46(m, 1H), 8.14 (s, 1H), 8.10 (td, J=9.0 Hz, 3.0 Hz, 1H), 4.44-4.39 (m,1H), 2.91 (s, 3H), 1.38-1.35 (m, 1H), 0.72-0.69 (m, 1H), 0.63-0.59 (m,2H), 0.40-0.47 (m, 1H). LC-MS m/z: 394.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=9.11 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4-fluoropyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 2-bromo-4-fluoropyridine afforded the titlecompound (4.3 mg, 2%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ8.87 (dd, J=8.4 Hz, 5.2 Hz, 1H), 8.74 (s, 1H), 8.50 (d, J=9.6 Hz, 1H),8.20 (s, 1H), 8.18 (dd, J=9.6 Hz, 2.4 Hz, 1H), 7.64-7.60 (m, 1H),4.50-4.42 (m, 1H), 2.92 (s, 3H), 1.37-1.30 (m, 1H), 0.74-0.67 (m, 1H),0.64-0.55 (m, 2H), 0.45-0.39 (m, 1H). LC-MS m/z: 394.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.94 min.

5-(3-Chloropyridin-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 2-bromo-3-chloropyridine (576 mg, 3 mmol) in toluene(20 mL) under N₂ was added dropwise n-BuLi (2.5 M, 1.32 mL, 3.3 mmol) at−78° C. The reaction mixture was stirred for 2 h, followed by theaddition of SnBu₃Cl (1.07 g, 3.3 mmol). The reaction mixture was stirred2 h at −78° C., warmed to RT and stirred another 2 h, and then quenchedwith saturated NH₄Cl solution (10 mL). The mixture was extracted with EA(30 mL×3), and the combined organic layers were washed with brine (15mL), dried (Na₂SO₄), and filtered. The filtrate was concentrated invacuo to afford 3-chloro-2-(tributylstannyl)pyridine (1.0 g, 83%) as acolorless oil. LC-MS m/z: 404.1 [M+H]⁺. t_(R)=2.04 min.

Following general procedure F,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 3-chloro-2-(tributylstannyl)pyridine afforded thetitle compound (42 mg, 52%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.79 (d, J=4.0 Hz, 1H), 8.74 (s, 1H), 8.48 (d J=9.5 Hz, 1H),8.23 (d, J=8.0 Hz, 1H), 7.90 (s, 1H), 7.67 (dd, J=8.0 Hz, 4.5 Hz, 1H),4.40-4.32 (m, 1H), 2.91 (s, 3H), 1.20-1.15 (m, 1H), 0.70-0.67 (m, 1H),0.63-0.60 (m, 1H), 0.58-0.51 (m, 1H), 0.35-0.31 (m, 1H). LC-MS m/z:410.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.78 min.

5-(4-Chloropyridin-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.21 mmol) and 4-chloro-2-(tributylstannyl)pyridine afforded thetitle compound (22 mg, 24%) as a yellow solid. ¹H NMR (500 MHz,MeOD-d₄): δ 8.75 (d, J=5.0 Hz, 1H), 8.68 (s, 1H), 8.54 (d, J=2.5 Hz,1H), 8.23 (s, 1H), 8.67 (dd, J=5.0 Hz, 2.0 Hz, 1H), 4.52-4.46 (m, 1H),2.98 (s, 3H), 1.37-1.32 (m, 1H), 0.83-0.78 (m, 1H), 0.72-0.68 (m, 1H),0.64-0.55 (m, 1H). LC-MS m/z: 410.0 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=9.54 min.

5-(5-Chloropyridin-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and 5-chloro-2-(tributylstannyl)pyridine affordedthe title compound (36 mg, 29%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.88 (d, J=2.0 Hz, 1H), 8.72 (s, 1H), 8.49 (d, J=9.5 Hz, 1H),8.41 (d, J=9.0 Hz, 1H), 8.30 (dd, J=8.5 Hz, 3.0 Hz, 1H), 8.15 (s, 1H),4.44-4.38 (m, 1H), 2.91 (s, 3H), 1.39-1.35 (m, 1H), 0.71-0.69 (m, 1H),0.64-0.61 (m, 2H), 0.41-0.39 (m, 1H). LC-MS m/z: 410.0 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=9.73 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(thiazol-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(90 mg, 0.27 mmol) and 2-(tributylstannyl)thiazole afforded the titlecompound (80 mg, 70%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.72 (s, 1H), 8.36 (d, J=9.5 Hz, 1H), 8.18 (d, J=3.0 Hz, 1H), 8.15 (d,J=3.0 Hz, 1H), 7.95 (s, 1H), 4.49-4.42 (m, 1H), 2.90 (s, 3H), 1.30-1.25(m, 1H), 0.72-0.67 (m, 1H), 0.66-0.56 (m, 2H), 0.48-0.41 (m, 1H). LC-MSm/z: 382.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.55 min.

(S)-5-(Benzo[d][1,3]dioxol-5-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(120 mg, 0.43 mmol) and2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneafforded the title compound (7.7 mg, 5%) as a yellow solid. ¹H NMR (400MHz, MeOD-d₄): δ 8.61 (d, J=7.2 Hz, 1H), 8.52 (s, 1H), 7.81 (d, J=8.0Hz, 1H), 7.77 (s, 1H), 7.62 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 6.10 (s,2H), 3.73-3.66 (m, 1H), 2.88 (s, 3H), 1.38 (d, J=6.8 Hz, 3H), 1.15-1.07(m, 1H), 0.68-0.55 (m, 2H), 0.51-0.45 (m, 1H), 0.42-0.36 (m, 1H). LC-MSm/z: 365.1 [M+H]⁺. HPLC Purity (214 nm): 96%; t_(R)=10.21 min.

5-(2-Cyanophenyl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol), and 2-cyanophenylboronic acid afforded the titlecompound (14 mg, 23%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.74 (s, 1H), 8.32 (d, J=9.5 Hz, 1H), 8.16-8.13 (m, 2H), 7.96 (d, J=7.5Hz, 1H), 7.83 (s, 1H), 7.80 (d, J=7.5 Hz, 1H), 4.30-4.25 (m, 1H), 2.90(s, 3H), 1.38-1.35 (m, 1H), 0.71-0.68 (m, 1H), 0.64-0.60 (m, 1H),0.51-0.48 (m, 1H), 0.34-0.31 (m, 1H). LC-MS m/z: 400.1 [M+H]⁺. HPLCPurity (214 nm): 98%; t_(R)=8.46 min.

(R)-5-(2-cyanophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(62 mg, 0.2 mmol) and 2-cyanophenylboronic acid afforded the titlecompound (25 mg, 33%) as a pale white solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.74 (s, 1H), 8.17-8.14 (m, 3H), 7.96 (t, J=8.0 Hz, 1H), 7.82 (s, 1H),7.80 (t, J=8.0 Hz, 1H), 5.01-4.97 (m, 1H), 2.89 (s, 3H), 1.43 (d, J=7.5Hz, 3H). LC-MS m/z: 374.1 [M+H]⁺. HPLC: Purity (214 nm): 97%; t_(R)=8.09min.

(S)-5-(2-Cyanophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.20 mmol) and 2-cyanophenylboronic acid afforded the titlecompound (18.8 mg, 26%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.75 (s, 1H), 8.17-8.14 (m, 3H), 7.96 (t, J=8.0 Hz, 1H), 7.82 (s, 1H),7.80 (t, J=8.0 Hz, 1H), 5.01-4.97 (m, 1H), 2.89 (s, 3H), 1.43 (d, J=7.5Hz, 3H). LC-MS m/z: 374.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.11 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(99 mg, 0.30 mmol) and 5-bromo-3-methylisothiazole afforded the titlecompound (7.6 mg, 7%) as a light brown solid. 1H NMR (500 MHz, DMSO-d₆)δ 8.71 (s, 1H), 8.26 (d, J=9.5 Hz, 1H), 8.08 (s, 1H), 7.91 (s, 1H),4.53-4.45 (m, 1H), 2.86 (s, 3H), 2.55 (s, 3H), 1.31-1.25 (m, 1H),0.74-0.69 (m, 1H), 0.65-0.55 (m, 2H), 0.45-0.40 (m, 1H). LC-MS m/z:396.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.78 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(101 mg, 0.30 mmol) and 5-bromo-3-methylisothiazole afforded the titlecompound (15 mg, 12%) as a light brown solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.71 (s, 1H), 8.26 (d, J=9.5 Hz, 1H), 8.08 (s, 1H), 7.91 (s, 1H),4.53-4.45 (m, 1H), 2.86 (s, 3H), 2.55 (s, 3H), 1.31-1.25 (m, 1H),0.74-0.69 (m, 1H), 0.65-0.55 (m, 2H), 0.45-0.40 (m, 1H). LC-MS m/z:396.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.78 min.

(S)-5-(Benzo[d]oxazol-7-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.25 mmol) and7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (28.3 mg, 20%) as a grey solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.98 (s, 1H), 8.61 (s, 1H), 8.28 (d, J=7.5 Hz, 1H), 8.26 (s,1H), 8.05 (d, J=7.5 Hz, 1H), 7.98 (s, 1H), 7.65 (t, J=7.5 Hz, 1H),3.68-3.63 (m, 1H), 2.89 (s, 3H), 1.33 (d, J=6.5 Hz, 3H), 1.12-1.08 (m,1H), 0.52-0.49 (m, 1H), 0.48-0.40 (m, 1H), 0.40-0.32 (m, 1H), 0.32-0.28(m, 1H). LC-MS m/z: 362.1 [M+H]⁺. HPLC Purity (214 nm): 98%; t_(R)=7.75min.

(R)-5-(Benzo[d]oxazol-7-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (67 mg, 62%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.99 (s, 1H), 8.62 (s, 1H), 8.28 (t, J=7.5 Hz, 1H), 8.26 (s,1H), 8.06 (d, J=7.5 Hz, 1H), 8.00 (s, 1H), 7.65 (t, J=7.5 Hz, 1H),3.68-3.63 (m, 1H), 2.90 (s, 3H), 1.33 (d, J=6.5 Hz, 3H), 1.12-1.08 (m,1H), 0.52-0.49 (m, 1H), 0.48-0.40 (m, 1H), 0.40-0.32 (m, 1H), 0.32-0.28(m, 1H). LC-MS m/z: 362.1 [M+H]⁺. HPLC: Purity (214 nm): 98%; t_(R)=7.72min.

5-(Benzo[d]oxazol-7-yl)-7-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (500 mg,2.37 mmol) and 1,1,1-trifluoro-2-methylpropan-2-amine hydrochlorideafforded5-chloro-7-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(310 mg, 41%) as a yellow solid. LC-MS m/z: 321.1 [M+H]⁺. Purity (214nm): >99%; t_(R)=1.95 min.

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.25 mmol) and7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (80 mg, 80%) as a brown solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.97 (s, 1H), 8.66 (s, 1H), 8.37 (s, 1H), 8.21 (d, J=7.5 Hz,1H), 8.06 (d, J=7.5 Hz, 1H), 8.01 (s, 1H), 7.66 (t, J=8.0 Hz, 1H), 2.92(s, 3H), 1.73 (s, 6H). LC-MS m/z: 404.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.48 min.

5-(Benzo[d]thiazol-5-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.32 mmol) and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole affordedthe title compound (55 mg, 42%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 9.54 (s, 1H), 8.97 (s, 1H), 8.68 (s, 1H), 8.58 (d, J=9.5 Hz,1H), 8.43 (d, J=8.5 Hz, 1H), 8.35 (dd, J=8.5 Hz, 1.0 Hz, 1H), 8.16 (s,1H), 5.02-4.98 (m, 1H), 2.89 (s, 3H), 1.49 (d, J=7.0 Hz, 3H). LC-MS m/z:406.0 [M+H]⁺. HPLC Purity (254 nm): 98%; t_(R)=8.22 min.

5-(Benzo[d]thiazol-7-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and 7-bromobenzo[d]thiazole (111 mg, 0.52 mmol)afforded the title compound (19 mg, 18%) as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 9.69 (s, 1H), 8.75 (s, 1H), 8.48 (d, J=7.5 Hz, 1H),8.38 (d, J=8.0 Hz, 1H), 8.19 (s, 1H), 8.15 (d, J=10.0 Hz, 1H), 7.85 (t,J=8.0 Hz, 1H), 5.13-5.09 (m, 1H), 2.90 (s, 3H), 1.52 (d, J=7.5 Hz, 3H).LC-MS m/z: 406.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.38 min.

(S)-5-(Benzo[d]thiazol-7-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.36 mmol) and 7-bromobenzo[d]thiazole afforded the titlecompound (24.6 mg, 18%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ9.72 (s, 1H), 8.64 (s, 1H), 8.47 (d, J=7.5 Hz, 1H), 8.36 (d, J=8.0 Hz,1H), 8.14 (s, 1H), 7.96 (d, J=8.5 Hz, 1H), 7.84 (t, J=7.5 Hz, 1H),3.65-3.61 (m, 1H), 2.89 (s, 3H), 1.38 (d, J=6.0 Hz, 3H), 1.18-1.14 (m,1H), 0.57-0.53 (m, 1H), 0.50-0.45 (m, 1H), 0.39-0.33 (m, 2H). LC-MS m/z:378.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.36 min.

5-(Benzo[d]oxazol-7-yl)-7-methyl-N-(2-cyclopropylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (500 mg,2.37 mmo) and 2-cyclopropylpropan-2-amine afforded5-chloro-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(600 mg, 87%) as a yellow solid. LC-MS m/z: 293.2 [M+H]⁺. Purity (214nm): >98%; t_(R)=1.98 min.

Following general procedure D,5-chloro-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.34 mmol) and7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazole affordedthe title compound (77 mg, 60%) as a grey solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.98 (s, 1H), 8.59 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 8.15 (s,1H), 8.06 (d, J=8.0 Hz, 1H), 7.97 (s, 1H), 7.65 (t, J=8.0 Hz, 1H), 2.91(s, 3H), 1.48-1.44 (m, 1H), 1.38 (s, 6H), 0.47-0.40 (m, 4H). LC-MS m/z:376.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.40 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-ethyl-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H, ethyl5-chloro-7-ethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (800 mg, 3.1mmol) and 1-iso-propylimidazolidin-2-one afforded ethyl7-ethyl-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(500 mg, 47%) as a brown solid. LC-MS m/z: 346.2 [M+H]⁺, t_(R)=1.82 min.

Following general procedure B*, ethyl7-ethyl-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(500 mg, 1.4 mmol) afforded7-ethyl-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid sodium salt (470 mg, 100%) as a yellow solid which was useddirectly in the next step. LC-MS m/z: 318.1 [M+H]⁺, t_(R)=1.24 min.

Following general procedure A,7-ethyl-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (100 mg, 0.29 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (33 mg, 26%) as a white solid.¹H NMR (400 MHz, MeOD-d₄) δ 8.41 (s, 1H), 8.22 (s, 1H), 4.36-4.30 (m,1H), 4.29-4.20 (m, 1H), 4.19-4.09 (m, 2H), 3.64 (t, J=8.0 Hz, 2H), 3.20(q, J=7.6 Hz, 2H), 1.45 (t, J=7.6 Hz, 3H), 1.27 (d, J=6.4 Hz, 6H),1.29-1.26 (m, 1H), 0.77-0.74 (m, 1H), 0.66-0.55 (m, 2H), 0.48-0.45 (m,1H). LC-MS m/z: 439.2 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=10.74min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (717 mg, 3mmol) and 1-iso-propylimidazolidin-2-one afforded ethyl5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(780 mg, 78%) as a pale solid. LC-MS m/z: 332.2 [M+H]⁺. LCMS: Purity(214 nm): 97.9%; t_(R)=1.27 min.

Following general procedure B*, ethyl5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(331 mg, 1.0 mmol) afforded5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (270 mg, 88%) as a solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.98 (s, 1H),7.75 (s, 1H), 6.68 (s, 1H), 2.45 (s, 3H), 2.43 (s, 3H). LC-MS m/z: 304.1[M+H]⁺. LCMS: Purity (254 nm): 81.9%; t_(R)=1.57 min.

Following general procedure A,5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (55 mg, 0.18 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (28 mg, 44%) as a white solid.¹H NMR (500 MHz, DMSO-d₆): δ 8.42 (s, 1H), 8.22 (d, J=9.5 Hz, 1H), 8.10(s, 1H), 4.38-4.30 (m, 1H), 4.13-4.03 (m, 2H), 4.00-3.95 (m, 1H),3.57-3.50 (m, 2H), 2.73 (s, 3H), 1.28-1.23 (m, 1H), 1.17 (d, J=7.0 Hz,6H), 0.68-0.64 (m, 1H), 0.57-0.54 (m, 2H), 0.35-0.32 (m, 1H). LC-MS m/z:425.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.85 min.

7-Ethyl-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-ethyl-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (100 mg, 0.29 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (20 mg, 17%) as a white solid. ¹H NMR (400MHz, MeOD-d₄) δ 8.42 (s, 1H), 8.21 (s, 1H), 4.93-4.90 (m, 1H), 4.25-4.12(m, 3H), 3.65 (t, J=8.0 Hz, 2H), 3.20 (q, J=7.2 Hz, 2H), 1.49 (d, J=7.2Hz, 3H), 1.46 (d, J=7.2 Hz, 3H), 3.65 (d, J=6.8 Hz, 6H). LC-MS m/z:413.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.90 min.

5-(3-iso-Propyl-2-oxoimidazolidin-1-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (50 mg, 0.15 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (15.6 mg, 24%) as a white solid. ¹H NMR (500MHz, DMSO-d₆), δ 8.43 (s, 1H), 8.13 (d, J=9.5 Hz, 1H), 8.09 (s, 1H),4.93-4.86 (m, 1H), 4.13-4.06 (m, 2H), 3.99-3.93 (m, 1H), 3.58-3.50 (m,2H), 2.73 (s, 3H), 1.40 (d, J=7.0 Hz, 3H), 1.17 (d, J=6.5 Hz, 6H). LC-MSm/z: 399.1 [M+H]⁺. HPLC: Purity (214 nm): 98%; t_(R)=8.13 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(2-oxoimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and imidazolidin-2-one afforded the title compound(15 mg, 13%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.43 (s,1H), 8.23 (d, J=10.0 Hz, 1H), 8.11 (s, 1H), 7.88 (s, 1H), 4.39-4.32 (m,1H), 4.18-4.10 (m, 1H), 4.08-4.02 (m, 1H), 3.54-3.50 (m, 2H), 2.74 (s,3H), 1.26-1.21 (m, 1H), 0.68-0.64 (m, 1H), 0.59-0.54 (m, 2H), 0.39-0.34(m, 1H). LC-MS m/z: 383.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.63min.

N-tert-Butyl-7-ethyl-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-ethyl-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (100 mg, 0.29 mmol) and 2-methylpropan-2-amine afforded the titlecompound (32 mg, 28%) as a yellow solid. ¹H NMR (400 MHz, MeOD-d₄) δ8.34 (s, 1H), 8.16 (s, 1H), 4.28-4.20 (m, 1H), 4.14 (t, J=8.0 Hz, 2H),3.69 (t, J=8.0 Hz, 2H), 3.17 (q, J=7.6 Hz, 2H), 1.51 (s, 9H), 1.44 (t,J=7.2 Hz, 3H), 1.26 (d, J=8.0 Hz, 6H). LC-MS m/z: 373.2 [M+H]⁺. HPLCPurity (214 nm): >99%, t_(R)=8.80 min.

N-(2-Cyclopropylpropan-2-yl)-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (50 mg, 0.16 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (1.5 mg, 3%) as a yellow solid. 1H NMR (500 MHz,MeOD-d₄): δ 8.35 (s, 1H), 8.11 (s, 1H), 4.25-4.22 (m, 1H), 4.12 (t,J=7.5 Hz, 2H), 3.61 (t, J=8.0 Hz, 2H), 2.75 (s, 3H), 1.42 (s, 6H),1.44-1.41 (m, 1H), 1.27 (d, J=6.5 Hz, 6H), 0.50-0.49 (m, 4H). LC-MS m/z:385.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.74 min.

5-(3-iso-Propyl-2-oxoimidazolidin-1-yl)-7-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (50 mg, 0.16 mmol) and 1,1,1-trifluoro-2-methylpropan-2-aminehydrochloride afforded the title compound (32 mg, 47%) as a yellowsolid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.37 (s, 1H), 8.10 (s, 1H), 7.99 (s,1H), 4.13-4.08 (m, 1H), 4.01 (t, J=7.5 Hz, 2H), 3.55 (t, J=8.0 Hz, 2H),2.73 (s, 3H), 1.67 (s, 6H), 1.16 (d, J=10.0 Hz, 6H). LC-MS m/z: 413.2[M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.89 min.

N-tert-Butyl-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (40 mg, 0.14 mmol) and 2-methylpropan-2-amine afforded the titlecompound (28 mg, 59%) as a white solid. ¹H NMR (400 MHz, MeOD-d₄): δ8.33 (s, 1H), 8.08 (s, 1H), 8.03 (s, 1H), 4.27-4.21 (m, 1H), 4.07 (t,J=8.0 Hz, 2H), 3.61 (t, J=8.0 Hz, 2H), 2.73 (d, J=0.4 Hz, 3H), 1.52 (s,9H), 1.27 (d, J=6.8 Hz, 6H). LC-MS m/z: 359.1 [M+H]⁺, 381.2[M+Na]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.32 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(2-oxo-3-(2,2,2-trifluoroethyl)imidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 2,2,2-trifluoroethanamine (6.0 g, 60.6 mmol) in MeCN(30 mL) was added 1-chloro-2-isocyanatoethane (7.0 g, 66.7 mmol). Thereaction mixture was stirred at RT for 4 h, and filtered to collect1-(2-chloroethyl)-3-(2,2,2-trifluoroethyl)urea (2.6 g, 22%) as a whitesolid. LC-MS m/z: 191.1 [M+H]⁺.

To a solution of 1-(2-chloroethyl)-3-(2,2,2-trifluoroethyl)urea (1.3 g,6.4 mmol) in THF (4 mL) was added NaH (305 mg, 7.6 mmol) at 0° C. Thereaction mixture was warmed to RT and stirred for 16 h, and quenchedwith saturated NH₄Cl (20 mL). The mixture was extracted with EA (10mL×3), and the combined organic layers were dried over anhydrous Na₂SO₄,and filtered. The filtrate was concentrated in vacuo to afford1-(2,2,2-trifluoroethyl)imidazolidin-2-one (500 mg, 47%) as a whitesolid. LC-MS m/z: 169.2 [M+H]⁺.

Following general procedure H,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 1-(2,2,2-trifluoroethyl)imidazolidin-2-oneafforded the title compound (50 mg, 40%) as an off white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 8.47 (s, 1H), 8.18 (d, J=9.6 Hz, 1H), 8.05 (s,1H), 4.34-4.28 (m, 1H), 4.19-4.02 (m, 3H), 3.72 (t, J=8.0 Hz, 2H), 2.76(s, 3H), 1.30-1.23 (m, 1H), 0.69-0.65 (m, 1H), 0.59-0.55 (m, 2H),0.35-0.30 (m, 1H). LC-MS m/z: 465.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.76 min.

(R)-5-(6-Chloropyridin-2-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(62 mg, 0.2 mmol) and2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineafforded the title compound (28 mg, 37%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.40-8.38 (m, 1H), 8.20 (t, J=8.0 Hz, 1H),8.05 (s, 1H), 7.61 (dd, J=8.0 Hz, 1.0 Hz, 1H), 5.01-4.96 (m, 1H), 2.92(s, 3H), 1.49 (d, J=7.5 Hz, 3H). LC-MS m/z: 384.1 [M+H]⁺. HPLC: Purity(214 nm): >99%; t_(R)=9.13 min.

(S)-5-(6-Chloropyridin-2-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(90 mg, 0.29 mmol) and2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineafforded the title compound (9.2 mg, 8%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.40-8.38 (m, 1H), 8.20 (t, J=8.0 Hz, 1H),8.05 (s, 1H), 7.61 (dd, J=8.0 Hz, 1.0 Hz, 1H), 5.01-4.96 (m, 1H), 2.92(s, 3H), 1.49 (d, J=7.5 Hz, 3H). LC-MS m/z: 384.1 [M+H]⁺. HPLC: Purity(214 nm): >99%; t_(R)=9.13 min.

5-(6-Chloropyridin-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and2-chloro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineafforded the title compound (29 mg, 30%) as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.74 (s, 1H), 8.50 (d, J=9.5 Hz, 1H), 8.39 (d, J=7.5Hz, 1H), 8.21 (d, J=8.0 Hz, 1H), 8.08 (s, 1H), 7.78 (d, J=8.0 Hz, 1H),4.44-4.40 (m, 1H), 2.93 (s, 3H), 1.40-1.36 (m, 1H), 0.72-0.67 (m, 1H),0.65-0.58 (m, 2H), 0.43-0.38 (m, 1H). LC-MS m/z: 410.0 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=10.05 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-ethyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxamide

Into the stirred solution of ethyl5-chloro-7-ethylpyrazolo[1,5-a]pyrimidine-3-carboxylate (0.2 g, 0.8mmol) and Cs₂CO₃ (1.3 g, 4.0 mmol) in DMF was added morpholine (87 mg,1.0 mmol). The mixture was stirred at 100° C. for 24 h, and concentratedin vacuo. The residue was purified by preparative TLC (PE:EA=1:1) toafford ethyl 7-ethyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 38%) as a brown solid. LC-MS m/z: 259.1 [M+H]⁺, t_(R)=1.21 min.

Following general procedure B*, ethyl7-ethyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylate (100 mg,0.39 mmol) afforded7-ethyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid sodiumsalt (117 mg, 100%) as a yellow solid which was used directly in thenext step. LC-MS m/z: 277.2 [M+H]⁺, t_(R)=1.07 min.

Following general procedure A,7-ethyl-5-morpholinopyrazolo[1,5-a]pyrimidine-3-carboxylic acid (117 mg,0.39 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanamine hydrochlorideafforded the title compound (21 mg, 13%) as a yellow solid. ¹H NMR (400MHz, MeOD-d₄) δ 8.27 (s, 1H), 6.68 (s, 1H), 4.38-4.35 (m, 1H), 3.84-3.76(m, 8H), 3.14-3.08 (m, 2H), 1.42 (t, J=8.0 Hz, 3H), 1.22-1.19 (m, 1H),0.74-0.72 (m, 1H), 0.63-0.59 (m, 1H), 0.52-0.43 (m, 2H). LC-MS m/z:397.8 [M+H]⁺. HPLC Purity (254 nm): >99%, t_(R)=8.19 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(isoxazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of tributyl(vinyl)stannane (1.142 g, 3.6 mmol), ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (717 mg, 3mmol), and Pd(PPh₃)₄(347 mg, 0.3 mmol) in dioxane (5 mL) was heated at100° C. under nitrogen atmosphere for 2 hours, cooled to roomtemperature and concentrated in vacuo after the addition of hydroquinone(10 mg). The resulting residue was purified by silica gel columnchromatography (PE/EA: 1/1) to afford ethyl7-methyl-5-vinylpyrazolo[1,5-a]pyrimidine-3-carboxylate (478 mg, 69%) asa solid. 1H NMR (500 MHz, CDCl₃) δ 8.54 (s, 1H), 7.01 (s, 1H), 6.94 (dd,J=17.5 Hz, 11.0 Hz 1H), 6.38 (d, J=17.5 Hz, 1H), 5.79 (d, J=11.0 Hz,1H), 4.42 (q, J=7.0 Hz, 2H), 2.83 (s, 3H), 1.43 (t, J=7.0 Hz, 3H). LC-MSm/z: 232.1 [M+H]⁺. LCMS: Purity (214 nm): 98.3%; t_(R)=1.72 min.

To a solution of ethyl7-methyl-5-vinylpyrazolo[1,5-a]pyrimidine-3-carboxylate (167 mg, 0.72mmol) and OsO₄ (2 mg, 0.007 mmol) in THF/H₂O (10 mL/3 mL) was addedNaIO₄ (616 mg, 2.89 mmol). The resulting mixture was stirred at RT for12 h, and diluted with H₂O (50 mL). The mixture was extracted with EA(20 mL×3), and the organic layers were washed with brine (15 mL), driedover anhydrous Na₂SO₄, and filtered. The filtrate was concentrated invacuo to afford ethyl5-formyl-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (150 mg), whichwas used directly in the next step. LC-MS m/z: 234.1 [M+H]⁺. LCMS:Purity (254 nm): 30%; t_(R)=1.65 min.

To a solution of ethyl5-formyl-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (150 mg) inMeOH (5 mL) were added hydroxylammonium chloride (108 mg, 1.45 mmol) andEt₃N (219 mg, 2.17 mmol). The mixture was stirred at RT for 2 h, andconcentrated in vacuo. The resulting residue was purified by silica gelcolumn chromatography (PE/EA: 1/2) to afford ethyl5-((hydroxyimino)methyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 55% two steps) as a yellow solid. LC-MS m/z: 271.0 [M+Na]⁺.LCMS: Purity (254 nm): 78%; t_(R)=1.08 min.

To a solution of ethyl5-((hydroxyimino)methyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 0.40 mmol) and ethynyltrimethylsilane (78 mg, 0.8 mmol) in MeCN(5 mL) was added CrO₂ (332 mg, 4.0 mmol). The reaction mixture wasstirred at 80° C. for 2 h, and filtered through Celite. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (PE/EA: 5/1) to afford ethyl7-methyl-5-(5-(trimethylsilyl)isoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(63 mg, 45%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.71 (s,1H), 7.83 (s, 1H), 7.29 (s, 1H), 4.32 (q, J=7.0 Hz, 2H), 2.87 (s, 3H),1.36 (t, J=7.0 Hz, 3H), 0.41 (s, 9H). LC-MS m/z: 345.1 [M+H]⁺. LCMS:Purity (254 nm): 88%; t_(R)=2.14 min.

Following general procedure A,5-(isoxazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(40 mg, 0.16 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (5.8 mg, 11%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (d, J=1.5 Hz, 1H), 8.74 (s, 1H),8.39 (d, J=10.0 Hz, 1H), 7.88 (s, 1H), 7.13 (d, J=2.0 Hz, 1H), 4.45-4.40(m, 1H), 2.90 (s, 3H), 1.38-1.35 (m, 1H), 0.70-0.67 (m, 1H), 0.60-0.58(m, 2H), 0.42-0.39 (m, 1H). LC-MS m/z: 366.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.34 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(isoxazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(isoxazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid(40 mg, 0.16 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (10 mg, 18%) as a white solid.¹H NMR (500 MHz, DMSO-d₆) δ 9.25 (d, J=1.5 Hz, 1H), 8.74 (s, 1H), 8.39(d, J=10.0 Hz, 1H), 7.88 (s, 1H), 7.13 (d, J=2.0 Hz, 1H), 4.45-4.40 (m,1H), 2.90 (s, 3H), 1.38-1.35 (m, 1H), 0.70-0.67 (m, 1H), 0.60-0.58 (m,2H), 0.42-0.39 (m, 1H). LC-MS m/z: 366.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.62 min.

(R)-5-(5-Cyano-2-methylfuran-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

The solution of methyl 5-methylfuran-2-carboxylate (1.5 g, 10.71 mmol)and AlCl₃ (2.14 g, 16.07 mmol) in 20 mL of chloroform was stirred at 0°C. for 30 minutes and then Br₂ (0.77 mL) was added at 0° C. The reactionmixture was stirred at 0° C. for 12 hours, poured into ice cubes (100 g)and extracted with DCM (50 mL×3). The organic layers were dried overanhydrous Na₂SO₄, and filtered. The filtrate was concentrated in vacuoto afford methyl 4-bromo-5-methylfuran-2-carboxylate (2.0 g, 86%).

Following general procedure E*,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 4-bromo-5-methylfuran-2-carbonitrile afforded thetitle compound (3.5 mg, 5%) as a yellow solid. ¹H NMR (500 MHz,MeOD-d₄): δ 8.62 (s, 1H), 7.94 (s, 1H), 7.47 (s, 1H), 4.32-4.27 (m, 1H),2.91 (s, 3H), 2.89 (s, 3H), 1.28-1.24 (m, 1H), 0.84-0.80 (m, 1H),0.68-0.62 (m, 2H), 0.47-0.43 (m, 1H). LC-MS m/z: 404.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=9.06 min.

(S)-5-(5-Cyano-2-methylfuran-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 4-bromo-5-methylfuran-2-carbonitrile afforded thetitle compound (12 mg, 13%) as a yellow solid. ¹H NMR (500 MHz,MeOD-d₄): δ 8.62 (s, 1H), 8.43 (d, J=9.5 Hz, 1H), 7.95 (s, 1H), 7.48 (s,1H), 4.33-4.28 (m, 1H), 2.91 (s, 3H), 2.89 (s, 3H), 1.28-1.23 (m, 1H),0.85-0.80 (m, 1H), 0.65-0.62 (m, 2H), 0.47-0.43 (m, 1H). LC-MS m/z:404.1 [M+H]⁺. HPLC Purity (214 nm): 94.6%; t_(R)=9.05 min.

5-(3-Cyano-5-methylfuran-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A, 5-methylfuran-3-carboxylic acid (1.26 g,10 mmol) and NH₄Cl afforded 5-methylfuran-3-carboxamide (700 mg, 56%) asa white solid. LC-MS m/z: 126.1 [M+H]⁺. LCMS: Purity (214 nm): 85.2%;t_(R)=1.28 min.

To a solution of 5-methylfuran-3-carboxamide (400 mg, 2.10 mmol), andEt₃N (1.7 g, 16.8 mmol) in DCM (20 mL) under N₂ was added POCl₃ (964 mg,6.3 mmol) dropwise at 0° C. The mixture was stirred at RT for 2 h,concentrated in vacuo and the residue was dissolved with EA (20 mL) andwashed with saturated NaHCO₃ solution (20 mL). The combined organiclayers were dried (Na₂SO₄), and filtered. The filtrate was concentratedin vacuo, and the residue was purified by silica gel columnchromatography (PE/EA: 4/1) to afford 5-methylfuran-3-carbonitrile (270mg, 75%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.79 (s, 1H), 6.20(s, 1H), 2.33 (s, 3H). LCMS: Purity (254 nm): 95%; t_(R)=1.68 min.

To a solution of 5-methylfuran-3-carbonitrile (321 mg, 3 mmol) in THF(10 mL) under N₂ was dropwise added n-BuLi (1.14 mL, 2.5 M in heptanes,2.85 mmol) at −78° C. The reaction mixture was stirred at −78° C. for0.5 h, followed by the addition of Bu₃SnCl (1.2 g, 3.6 mmol). Thereaction mixture was stirred at −78° C. for 2 h, allowed to stir at RTfor another 2 h, and quenched with NH₄Cl (10 mL). The reaction mixturewas extracted with EA (50 mL×3) and the combined organic layers werewashed with brine (30 mL), dried (Na₂SO₄) and filtered. The filtrate wasconcentrated in vacuo to afford5-methyl-2-(tributylstannyl)furan-3-carbonitrile (1.25 g, crude), whichwas used in the next step without purifications. LC-MS m/z: 420.1[M+H]⁺. LCMS: t_(R)=2.17 min.

Following general procedure F,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and 5-methyl-2-(tributylstannyl)furan-3-carbonitrileafforded the title compound (90 mg, 75%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆) $8.73 (s, 1H), 7.99 (d, J=9.5 Hz, 1H), 7.68 (s, 1H), 6.97(s, 1H), 4.19-4.16 (m, 1H), 2.88 (s, 3H), 2.45 (s, 3H), 1.60-1.53 (m,1H), 0.71-0.63 (m, 2H), 0.54-0.53 (m, 1H), 0.26-0.24 (m, 1H). LC-MS m/z:404.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=9.16 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 2-methyloxazole (1.0 g, 12.0 mmol) in Et₂O (20 mL) wasadded n-BuLi (6.24 mL, 2.5M, 15.6 mmol) dropwise at −78° C. Afterstirring for 2 h, a solution of Bu₃SnCl (3.59 g, 11.0 mmol) in Et₂O (10mL) was added dropwise at −78° C. The reaction was allowed to warm to RTand stirred overnight. Then the reaction was quenched with saturatedNH₄Cl (25 mL) and then extracted with Et₂O (50 mL×2). The combinedorganic layers were dried over anhydrous Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo to afford2-methyl-5-(tributylstannyl)oxazole (3.5 g, 77%) as a yellow oil, whichwas used directly in the next step.

Following general procedure A,7-methyl-5-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.12 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (15 mg, 32%) as a yellowsolid. ¹H NMR (400 MHz, MeOD-d₄): δ 8.56 (s, 1H), 7.90 (s, 1H), 7.53 (s,1H), 4.52-4.48 (m, 1H), 2.90 (s, 3H), 2.63 (s, 3H), 1.36-1.30 (m, 1H),0.77-0.73 (m, 1H), 0.69-0.65 (m, 1H), 0.61-0.53 (m, 2H). LC-MS m/z:380.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.78 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.12 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (21 mg, 46%) as a yellowsolid. ¹H NMR (400 MHz, MeOD-d₄): δ 8.56 (s, 1H), 7.90 (s, 1H), 7.53 (s,1H), 4.52-4.48 (m, 1H), 2.90 (s, 3H), 2.63 (s, 3H), 1.36-1.30 (m, 1H),0.77-0.73 (m, 1H), 0.69-0.65 (m, 1H), 0.61-0.53 (m, 2H). LC-MS m/z:380.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.78 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(2-methyloxazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution of ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1.0 g, 3.6mmol) and tributyl(1-ethoxyvinyl)stannane (2.1 g, 5.4 mmol) in dioxane(10 mL) was added Pd(PPh₃)₂Cl₂ (253 mg, 0.36 mmol). The reaction mixturewas stirred for 3 h at 110° C. under N₂. The product was purified bysilica gel column chromatography (PE/EA=3/1) to afford ethyl5-(1-ethoxyvinyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (891mg, 90%) as a white solid. LC-MS m/z: 276.1 [M+H]⁺.

To a stirred solution of ethyl5-(1-ethoxyvinyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (880mg, 3.2 mmol) in THF/H₂O (10 mL/1 mL) was added NBS (627 mg, 3.5 mmol).The reaction mixture was stirred for 3 h at RT, and filtered to removethe solid. The cake was washed with CH₃CN (10 mL), and the filtrated wasconcentrated in vacuo to afford ethyl5-(2-bromoacetyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (800mg, 77%) as a yellow solid. LC-MS m/z: 328.0 [M+H]⁺.

A solution of ethyl5-(2-bromoacetyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (800mg, 2.5 mmol) and acetamide (1.5 g, 25 mmol) in DMF (5 mL) was stirredfor 4 h at 110° C. The product was purified by silica gel columnchromatography (PE/EA=3/1) to afford ethyl7-methyl-5-(2-methyloxazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(140 mg, 20%) as a yellow solid. LC-MS m/z: 287.1 [M+H]⁺.

Following general procedure B*, ethyl7-methyl-5-(2-methyloxazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(140 mg, 0.49 mmol) afforded7-methyl-5-(2-methyloxazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (115 mg, 91%) as a yellow solid. LC-MS m/z: 259.1 [M+H]⁺.

Following general procedure A,7-methyl-5-(2-methyloxazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (40 mg, 0.16 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (14 mg, 23%) as a white solid.¹H NMR (500 MHz, DMSO-d₆): δ 8.74 (s, 1H), 8.64 (s, 1H), 8.43 (d, J=9.5Hz, 1H), 7.68 (s, 1H), 4.40-4.34 (m, 1H), 2.85 (s, 3H), 2.55 (s, 3H),1.46-1.41 (m, 1H), 0.70-0.60 (m, 1H), 0.59-0.56 (m, 2H), 0.45-0.42 (m,1H). LC-MS m/z: 380.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.40min.

5-(3-Cyanofuran-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To an ice cold solution of 2,2,6,6-tetramethylpiperidine (1.9 g, 13.5mmol) in THF (15 mL) was added BuLi (2.5M in hexanes, 4.8 mL, 12.0 mmol)slowly. The solution was stirred at 0° C. for 30 min, and cooled to −78°C. A solution of furan-3-carbonitrile (1.4 g, 15.0 mmol) in THF (10 mL)was added dropwise over 30 min and the mixture was stirred for 2 h at−78° C. A solution of SnBu₃Cl in THF (5 mL, 18 mmol) was added dropwiseover 30 min and the mixture was stirred overnight with the temperaturerising to RT during that time. The reaction was quenched with saturatedNH₄Cl (20 mL) and extracted with DCM (30 mL×3). The organic layers weredried over anhydrous Na₂SO₄, and filtered. The filtrate was concentratedin vacuo, and the residue was purified by silica gel columnchromatography (PE/EA=100:1) to afford2-(tributylstannyl)furan-3-carbonitrile (3.7 g, 63%) as a colorless oil.LC-MS m/z: no MS signal. t_(R)=2.65 min.

Following general procedure F,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(111 mg, 0.33 mmol) and 2-(tributylstannyl)furan-3-carbonitrile affordedthe title compound (34 mg, 26%) as a light yellow solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.73 (s, 1H), 8.31 (d, J=1.5 Hz, 1H), 7.98 (d, J=11.5Hz, 1H), 7.73 (s, 1H), 7.34 (d, J=2.0 Hz, 1H), 4.23-4.12 (m, 1H), 2.88(s, 3H), 1.61-1.52 (m, 1H), 0.75-0.63 (m, 2H), 0.56-0.49 (m, 1H),0.28-0.22 (m, 1H). LC-MS m/z: 390.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.49 min.

N-(2-Cyclopropylpropan-2-yl)-7-methyl-5-(2-methyloxazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(2-methyloxazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (40 mg, 0.16 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (19 mg, 35%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆):δ 8.64 (s, 1H), 8.51 (s, 1H), 7.98 (s, 1H), 7.61 (s, 1H), 2.83 (s, 3H),2.54 (s, 3H), 1.44-1.42 (m, 1H), 1.37 (s, 6H), 0.48-0.46 (m, 4H). LC-MSm/z: 340.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.39 min.

N-(2-Cyclopropylpropan-2-yl)-7-methyl-5-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (127 mg, 0.49 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (20 mg, 15%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆):δ 8.50 (s, 1H), 8.000 (s, 1H), 7.997 (d, J=2.4 Hz, 1H), 7.59 (s, 1H),2.80 (s, 3H), 2.56 (s, 3H), 1.37 (s, 6H), 1.36-1.33 (m, 1H), 0.49 (d,J=6.8 Hz, 4H). LC-MS m/z: 340.2 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=7.80 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(5-methyloxazol-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 5-methyloxazole (160 mg, 2.0 mmol) in THF (10 mL) wasadded n-BuLi (2.5 mmol, 1.0 mL, 2.5 M) at −78° C. under N₂ and themixture was stirred for 20 min, followed by the addition of ZnCl₂(2.0mmol, 2 mL ether solution, 1M). The solution was then stirred at −78° C.under N₂ for another 30 min, warmed to RT and5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(166 mg, 0.5 mmol) and Pd(PPh₃)₂Cl₂ (70 mg, 0.1 mmol) were added. Themixture was stirred at 60° C. under N₂ for 5 h, concentrated in vacuoand purified by preparative HPLC (10 mM NH₄HCO₃/MeCN)) to afford thetitle compound (24 mg, 13%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄):δ 8.66 (s, 1H), 7.78 (s, 1H), 7.18 (d, J=0.8 Hz, 1H), 4.56-4.51 (m, 1H),2.94 (s, 3H), 2.52 (d, J=0.8 Hz, 3H), 1.40-1.35 (m, 1H), 0.77-0.71 (m,1H), 0.70-0.64 (m, 2H), 0.52-0.52 (m, 1H). LC-MS m/z: 380.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.48 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 4-methyloxazole (160 mg, 2.0 mmol) in anhydrous THF (10mL) was added BuLi (2.5 mmol, 1.0 mL, 2.5M solution in hexane) dropwiseat −78° C. under N₂. The mixture was stirred at −78° C. for 0.5 h,followed by the dropwise addition of ZnCl₂(2.5 mmol, 2.5 mL, 1M solutionin ether) at −78° C. After stirring at −78° C. for 2 h, the reactionmixture was allowed to warm to RT, and to this was added(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(330 mg, 1.0 mmol), and Pd(PPh₃)₂Cl₂ (30 mg, 0.05 mmol). The resultingmixture was stirred at 70° C. under N₂ for 24 h, and concentrated invacuo. The residue was purified by preparative HPLC (10 mM NH₃/MeCN) toafford the title compound (5 mg, 3%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.73 (s, 1H), 8.46 (d, J=10.0 Hz, 1H), 8.23 (d, J=1.2 Hz,1H), 7.88 (s, 1H), 4.61-4.52 (m, 1H), 2.87 (s, 3H), 2.52 (s, 3H),1.28-1.18 (m, 1H), 0.70-0.48 (m, 4H). LC-MS m/z: 380.1 [M+H]⁺. HPLC:Purity (214 nm): 92%, t_(R)=8.40 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(4-methyloxazol-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 4-methyloxazole (85 mg, 1.0 mmol) in THF (5 mL) wasadded dropwise n-BuLi (2.5M in n-hexane, 0.44 mL, 1.1 mmol) at −78° C.The resulting solution was stirred for 0.5 h at −78° C., followed by theaddition of ZnCl₂ (1.0M in Et₂O, 4.4 mL, 4.4 mmol), and warmed to RT. Tothe reaction mixture were added(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(99 mg, 0.30 mmol) and Pd(PPh₃)₂Cl₂ (25 mg, 0.03 mmol). The mixture thenstirred for 2 h at 60° C., quenched with saturated NH₄Cl solution (50mL) and extracted with EA (30 mL×3). The organic layers were washed withH₂O (50 mL), dried over anhydrous Na₂SO₄, and filtered. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (10/1 of EA/MeOH) to afford the title compound (9 mg, 8%)as a white solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.72 (s, 1H), 8.46 (d,J=9.5 Hz, 1H), 8.23 (d, J=1.0 Hz, 1H), 7.88 (s, 1H), 4.60-4.53 (m, 1H),2.88 (s, 3H), 2.25 (d, J=0.5 Hz, 3H), 1.26-1.21 (m, 1H), 0.69-0.52 (m,4H). LC-MS m/z: 380.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.47min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1.7 g, 7.04mmol) and 1-iso-propyltetrahydropyrimidin-2(1H)-one afforded ethyl5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(600 mg, 25%) as a grey oil. LC-MS m/z: 346.2 [M+H]⁺, t_(R)=1.74 min.

Following general procedure B*, ethyl5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(600 mg, 1.74 mmol) afforded5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid sodium salt (590 mg, 99%) as a light green solid which was useddirectly in the next step. LC-MS m/z: 318.1[M+H]⁺, t_(R)=1.19 min.

Following general procedure A,5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid sodium salt (200 mg, 0.59 mmol) and1-cyclopropyl-2,2,2-trifluoroethanamine hydrochloride afforded the titlecompound (42 mg, 16%) as a pink solid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.45(s, 1H), 8.23 (d, J=10.0 Hz, 1H), 8.80 (s, 1H), 4.65-4.60 (m, 1H),4.39-4.34 (m, 1H), 3.98-3.91 (m, 2H), 3.29 (t, J=6.0 Hz, 2H), 2.72 (s,3H), 2.07-2.02 (m, 2H), 1.23-1.21 (m, 1H), 1.14 (d, J=6.5 Hz, 6H),0.69-0.65 (m, 1H), 0.58-0.55 (m, 2H), 0.37-0.33 (m, 1H). LC-MS m/z:438.8 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.72 min.

N-tert-Butyl-5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (63 mg, 0.11 mmol) and 2-methylpropan-2-amine afforded the titlecompound (3.0 mg, 4%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆): δ8.33 (s, 1H), 7.79 (s, 1H), 7.75 (d, J=0.5 Hz, 1H), 4.65-4.61 (m, 1H),3.96 (t, J=6.0 Hz, 2H), 3.28 (t, J=6.0 Hz, 2H), 2.70 (s, 3H), 2.06-2.02(m, 1H), 1.42 (s, 9H), 1.15 (d, J=7.0 Hz, 6H). LC-MS m/z: 372.9 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=8.20 min.

5-(3-iso-Propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.09 mmol) and 1,1,1-trifluoropropan-2-amine hydrochlorideafforded the title compound (7.2 mg, 19%) as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.45 (s, 1H), 8.15 (d, J=9.0 Hz, 1H), 7.79 (s, 1H),4.93-4.87 (m, 1H), 4.65-4.60 (m, 1H), 4.01-3.97 (m, 1H), 3.93-3.88 (m,1H), 3.29 (t, J=6.0 Hz, 2H). LC-MS m/z: 413.2 [M+H]⁺. HPLC Purity (214nm): 99%; t_(R)=8.30 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(2-oxo-3-(2,2,2-trifluoroethyl)tetrahydropyrimidin-1(2H)-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 2,2,2-trifluoroethanamine (1.5 g, 15 mmol) in MeCN (10mL) was added 1-chloro-3-isocyanatopropane (2.2 g, 18 mmol). Thereaction mixture was stirred at RT for 4 h, and filtered to afford1-(3-chloropropyl)-3-(2,2,2-trifluoroethyl)urea (1.3 g, 39%) as a whitesolid.

To a solution of 1-(3-chloropropyl)-3-(2,2,2-trifluoroethyl)urea (1.3 g,5.9 mmol) in THF (4 mL) was added NaH (477 mg, 11.9 mmol) at 0° C. Thereaction mixture was warmed to RT and stirred for 16 h, and quenchedwith saturated NH₄Cl (20 mL). The mixture was extracted with EA (10mL×3), and the combined organic layers were dried over anhydrous Na₂SO₄,and filtered. The filtrate was concentrated in vacuo to afford1-(2,2,2-trifluoroethyl)tetrahydropyrimidin-2(1H)-one (600 mg, 56%) as awhite solid.

Following general procedure H,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and1-(2,2,2-trifluoroethyl)tetrahydropyrimidin-2(1H)-one afforded the titlecompound (60 mg, 27%) as a white solid. ¹H NMR (500 MHz, CDCl₃): δ 8.55(s, 1H), 8.11 (d, J=10.0 Hz, 1H), 7.80 (d, J=1.0 Hz, 1H), 4.50-4.44 (m,1H), 4.18-4.05 (m, 4H), 3.64-3.61 (m, 2H), 2.78 (s, 3H), 2.26-2.19 (m,2H), 1.12-1.10 (m, 1H), 0.71-0.69 (m, 1H), 0.56-0.52 (m, 3H). LC-MS m/z:478.7 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.62 min.

N-(2-Cyclopropylpropan-2-yl)-5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.09 mmol) and 2-cyclopropylpropan-2-amine afforded thetitle compound (11.5 mg, 32%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.32 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.75 (s, 1H),4.62-4.58 (m, 1H), 3.97 (t, J=6.0 Hz, 2H), 3.28 (t, J=6.0 Hz, 2H), 2.69(s, 3H), 2.06-2.00 (m, 2H), 1.39-1.33 (m, 1H), 1.32 (s, 6H), 1.14 (d,J=6.8 Hz, 6H), 0.42-0.37 (m, 4H). LC-MS m/z: 399.2 [M+H]⁺. HPLC Purity(214 nm): 99%; t_(R)=8.53 min.

5-(3-Iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methyl-N-(1,1,1-trifluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-iso-propyl-2-oxotetrahydropyrimidin-1(2H)-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.09 mmol) and 1,1,1-trifluoro-2-methylpropan-2-aminehydrochloride afforded the title compound (4.5 mg, 12%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.38 (s, 1H), 8.00 (s, 1H), 7.77 (s,1H), 4.63-4.60 (m, 2H), 3.92 (t, J=5.5 Hz, 2H), 3.30-3.27 (m, 2H), 2.70(s, 3H), 2.06-2.01 (m, 2H), 1.66 (s, 6H), 1.14 (d, J=7.0 Hz, 6H). LC-MSm/z: 427.1 [M+H]⁺. HPLC Purity (214 nm): 97%; t_(R)=8.73 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4-methoxypyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and 4-methoxypyridin-3-ylboronic acid afforded thetitle compound (29 mg, 24%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆):δ 8.87 (s, 1H), 8.68 (s, 1H), 8.61 (d, J=6.0 Hz, 1H), 8.46 (d, J=9.5 Hz,1H), 7.73 (d, J=1.0 Hz, 1H), 7.33 (d, J=6.0 Hz, 1H), 4.52-4.47 (m, 1H),4.00 (s, 3H), 2.86 (d, J=0.5 Hz, 3H), 1.20-1.16 (m, 1H), 0.68-0.65 (m,1H), 0.57-0.54 (m, 2H), 0.38-0.34 (m, 1H). LC-MS m/z: 406.0 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=7.57 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-fluorofuran-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 5-bromofuran-2-carboxylic acid (3 g, 15.8 mmol) and sodiumbicarbonate (3.3 g, 39.5 mmol) was stirred in 135 mL of pentane/water(2/5) at room temperature for 30 minutes, followed by the addition of1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis-tetrafluoroborate(5.6 g, 15.8 mmol). The mixture was stirred for another hour at roomtemperature, and separated to afford the pentane solution of5-bromo-2-fluorofuran, which was dried (MgSO₄), diluted with 20 mL ofanhydrous THF, and cooled to −78° C. under nitrogen. To this was addedn-butyllithium (2.6M, 3.2 mL, 7.9 mmol). The mixture was stirred at −78°C. for 30 minutes, followed by the addition of tri-n-butylstannylchloride (2.6 g, 7.9 mmol). The mixture was then allowed to stir at roomtemperature for another 20 minutes, quenched with saturated NH₄Cl (100mL), and separated. The organic phase was dried over anhydrous MgSO₄,and filtered. The filtrate was concentrated in vacuo to affordtributyl(5-fluorofuran-2-yl)stannane (3.0 g) as a brown oil, which wasused for the next step without further purification.

Following general procedure F,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.33 mmol) and tributyl(5-fluorofuran-2-yl)stannane affordedthe title compound (58.3 mg, 49%) as a white solid. 1H NMR (400 MHz,DMSO-d₆) δ 8.60 (s, 1H), 8.46 (d, J=9.6 Hz, 1H), 7.61 (s, 1H), 7.56 (t,J=3.6 Hz, 1H), 6.24 (dd, J=6.8 Hz, 3.6 Hz, 1H), 4.57-4.46 (m, 1H), 2.81(s, 3H), 1.31-1.26 (m, 1H), 0.70-0.41 (m, 4H). LC-MS m/z: 383.1 [M+H]⁺.HPLC: Purity (214 nm): 98%; t_(R)=9.02 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-methoxypyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmmol) and3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineafforded the title compound (18 mg, 29%) as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 9.03 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 8.51 (d, J=2.5Hz, 1H), 8.50 (d, J=9.5 Hz, 1H), 8.11 (dd, J=2.5 Hz, 2.0 Hz, 1H), 8.08(s, 1H), 4.50-4.48 (m, 1H), 3.96 (s, 3H), 2.88 (s, 3H), 1.29-1.22 (m,1H), 0.70-0.67 (m, 1H), 0.60-0.56 (m, 2H), 0.40-0.38 (m, 1H). LC-MS m/z:406.1 [M+H]⁺. HPLC: Purity (214 nm): 99%; t_(R)=7.99 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-methoxypyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmmol) and3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineafforded the title compound (16 mg, 26%) as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 9.03 (d, J=1.5 Hz, 1H), 8.70 (s, 1H), 8.51 (d, J=2.5Hz, 1H), 8.50 (d, J=9.5 Hz, 1H), 8.11 (dd, J=2.5 Hz, 2.0 Hz, 1H), 8.08(s, 1H), 4.50-4.48 (m, 1H), 3.96 (s, 3H), 2.88 (s, 3H), 1.29-1.22 (m,1H), 0.70-0.67 (m, 1H), 0.60-0.56 (m, 2H), 0.40-0.38 (m, 1H). LC-MS m/z:406.1 [M+H]⁺. HPLC: Purity (214 nm): 99%; t_(R)=8.00 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(6-methoxypyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 6-methoxypyridin-3-ylboronic acid afforded thetitle compound (74 mg, 76%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.07 (d, J=2.5 Hz, 1H), 8.64 (s, 1H), 8.52 (d, J=9.5 Hz,1H), 8.49 (dd, J=8.5 Hz, 3.0 Hz, 1H), 7.95 (s, 1H), 7.09 (d, J=9.0 Hz,1H), 4.46-4.43 (m, 1H), 3.98 (s, 3H), 2.85 (s, 3H), 1.31-1.28 (m, 1H),0.70-0.68 (m, 1H), 0.60-0.58 (m, 2H), 0.40-0.37 (m, 1H). LC-MS m/z:406.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.87 min.

5-(4-Methoxypyridin-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.33 mmol) and 4-methoxypyridin-3-ylboronic acid afforded thetitle compound (42.5 mg, 34%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.88 (s, 1H), 8.68 (s, 1H), 8.61 (d, J=6.0 Hz, 1H), 8.42 (d,J=9.0 Hz, 1H), 7.73 (s, 1H), 7.32 (d, J=5.5 Hz, 1H), 4.97-4.92 (m, 1H),4.00 (s, 3H), 2.86 (s, 3H), 1.39 (d, J=7.0 Hz, 3H). LC-MS m/z: 380.1[M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.12 min.

5-(5-Methoxypyridin-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(90 mg, 0.29 mmol) and3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridineafforded the title compound (64 mg, 65%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.69 (s, 1H), 8.50 (d, J=3.0 Hz, 1H), 8.41(d, J=9.0 Hz, 1H), 8.12 (s, 1H), 8.07 (s, 1H), 5.01-4.95 (m, 1H), 3.96(s, 3H), 2.88 (s, 3H), 1.45 (d, J=7.0 Hz, 3H). LC-MS m/z: 380.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=7.61 min.

(R)-5-(6-Methoxypyridin-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.23 mmol) and 6-methoxypyridin-3-ylboronic acid afforded thetitle compound (43 mg, 49%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.05 (d, J=2.0 Hz, 1H), 8.63 (s, 1H), 8.46 (dd, J=9.0 Hz,2.5 Hz, 1H), 8.41 (d, J=9.5 Hz, 1H), 7.91 (s, 1H), 7.07 (d, J=8.5 Hz,1H), 4.99-4.94 (m, 1H), 3.97 (s, 3H), 2.84 (s, 3H), 1.46 (d, J=6.5 Hz,3H). LC-MS m/z: 380.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.40min.

(S)-5-(6-Methoxypyridin-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(110 mg, 0.35 mmol) and 6-methoxypyridin-3-ylboronic acid afforded thetitle compound (55 mg, 40%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.07 (d, J=2.0 Hz, 1H), 8.64 (s, 1H), 8.49 (dd, J=8.5 Hz,2.5 Hz, 1H), 8.42 (d, J=9.5 Hz, 1H), 7.94 (s, 1H), 7.10 (d, J=8.5 Hz,1H), 5.00-4.94 (m, 1H), 3.98 (s, 3H), 2.85 (s, 3H), 1.46 (d, J=6.5 Hz,3H). LC-MS m/z: 380.1 [M+H]⁺. HPLC: Purity (214 nm): 99.39%; t_(R)=8.93min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(4-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 4-methylpyridin-3-ylboronic acid afforded thetitle compound (3.6 mg, 4%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.80 (s, 1H), 8.72 (s, 1H), 8.59 (d, J=5.0 Hz, 1H), 8.34 (d,J=9.0 Hz, 1H), 7.66 (s, 1H), 7.47 (d, J=5.0 Hz, 1H), 4.41-4.38 (m, 1H),2.88 (s, 3H), 2.57 (s, 3H), 1.17-1.15 (m, 1H), 0.66-0.51 (m, 3H),0.32-0.29 (m, 1H). LC-MS m/z: 390.1 [M+H]⁺. HPLC: Purity (214 nm): 99%;t_(R)=7.78 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(5-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(75 mg, 0.23 mmol) and 5-methylpyridin-3-ylboronic acid afforded thetitle compound (25 mg, 28%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆)δ 9.23 (d, J=2.0 Hz, 1H), 8.68 (s, 1H), 8.64 (d, J=1.0 Hz, 1H), 8.54 (d,J=9.5 Hz, 1H), 8.40 (s, 1H), 8.03 (s, 1H), 4.55-4.51 (m, 1H), 2.88 (s,3H), 2.43 (s, 3H), 1.31-1.26 (m, 1H), 0.71-0.67 (m, 1H), 0.62-0.55 (m,2H), 0.43-0.40 (m, 1H). LC-MS m/z: 390.1 [M+H]⁺. HPLC: Purity (214nm): >98%; t_(R)=8.11 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(5-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(67 mg, 0.20 mmol) and 5-methylpyridin-3-ylboronic acid afforded thetitle compound (35 mg, 45%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.23 (d, J=2.0 Hz, 1H), 8.69 (s, 1H), 8.64 (d, J=1.2 Hz, 1H), 8.55 (d,J=9.6 Hz, 1H), 8.41 (s, 1H), 8.04 (s, 1H), 4.52 (q, J=8.0 Hz, 1H), 2.88(s, 3H), 2.43 (s, 3H), 1.31-1.27 (m, 1H), 0.71-0.67 (m, 1H), 0.61-0.57(m, 2H), 0.43-0.39 (m, 1H). LC-MS m/z: 390.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.12 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (239 mg, 1.0mmol) and 6-methylpyridin-3-ylboronic acid afforded ethyl7-methyl-5-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(150 mg, 50%) as a yellow solid. LC-MS m/z: 297.1 [M+H]⁺. t_(R)=1.65min.

Following general procedure B*, ethyl7-methyl-5-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(150 mg, 0.506) afforded7-methyl-5-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (110 mg, 81%) as a yellow solid. LC-MS m/z: 269.1 [M+H]⁺.t_(R)=1.14 min.

Following general procedure A,7-methyl-5-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (60 mg, 0.22 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the tile compound (44 mg, 38%) as a white solid.¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (d, J=2.5 Hz, 1H), 8.67 (s, 1H), 8.53(d, J=9.5 Hz, 1H), 8.46 (dd, J=8.0 Hz, 2.0 Hz, 1H), 8.00 (s, 1H), 7.53(d, J=8.0 Hz, 1H), 4.56-4.40 (m, 1H), 2.87 (s, 3H), 2.59 (s, 3H),1.36-1.23 (m, 1H), 0.77-0.54 (m, 3H), 0.42-0.35 (m, 1H). LC-MS m/z:390.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.05 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluorethyl)-7-methyl-5-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,7-methyl-5-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (55 mg, 0.205 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (24 mg, 30%) as a yellowsolid. ¹H NMR (500 MHz, MeOD-d₄) δ 9.28 (d, J=2.5 Hz, 1H), 8.65 (s, 1H),8.52 (dd, J=8.5 Hz, 2.0 Hz, 1H), 7.81 (d, J=0.5 Hz, 1H), 7.56 (d, J=8.0Hz, 1H), 4.46-4.42 (m, 1H), 2.96 (s, 3H), 2.67 (s, 3H), 1.35-1.31 (m,1H), 0.81-0.76 (m, 1H), 0.72-0.62 (m, 1H), 0.61-0.58 (m, 1H), 0.52-0.49(m, 4H). LC-MS m/z: 390.1 [M+H]⁺. HPLC: Purity (214 nm): 97.01%;t_(R)=8.05 min.

7-Methyl-5-(4-methylpyridin-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and 4-methylpyridin-3-ylboronic acid afforded thetitle compound (18.2 mg, 19%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.81 (s, 1H), 8.72 (s, 1H), 8.59 (d, J=5.0 Hz, 1H), 8.24 (d,J=9.5 Hz, 1H), 7.67 (s, 1H), 7.48 (d, J=5.0 Hz, 1H), 4.98-4.94 (m, 1H),2.87 (s, 3H), 2.56 (s, 3H), 1.36 (d, J=7.0 Hz, 3H). LC-MS m/z: 364.1[M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=7.35 min

7-Methyl-5-(5-methylpyridin-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and 5-methylpyridin-3-ylboronic afforded the titlecompound (11.2 mg, 12%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ9.24 (d, J=2.0 Hz, 1H), 8.69 (s, 1H), 8.64 (s, 1H), 8.49 (d, J=9.0 Hz,1H), 8.42 (s, 1H), 8.04 (s, 1H), 5.02-4.95 (m, 1H), 2.88 (s, 3H), 2.44(s, 3H), 1.46 (d, J=7.0 Hz, 3H). LC-MS m/z: 364.1 [M+H]⁺. HPLC: Purity(214 nm): >99%; t_(R)=7.67 min.

7-Methyl-5-(6-methylpyridin-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.327 mmol) and 6-methylpyridin-3-ylboronic acid afforded thetitle compound (8.2 mg, 7%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄)δ 9.27 (d, J=2.0 Hz, 1H), 8.64 (s, 1H), 8.52 (dd, J=8.5 Hz, 2.5 Hz, 1H),7.79 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 5.00-4.97 (m, 1H), 2.95 (s, 3H),2.67 (s, 3H), 1.54 (d, J=7.0 Hz, 3H). LC-MS m/z: 364.1 [M+H]⁺. HPLC:Purity (254 nm): >99%; t_(R)=6.46 min.

7-Methyl-5-(4-(trifluoromethyl)pyridin-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(90 mg, 0.29 mmol) and 3-bromo-4-(trifluoromethyl)pyridine afforded thetitle compound (10 mg, 8%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆)δ 9.10 (s, 1H), 9.07 (d, J=5.0 Hz, 1H), 8.78 (s, 1H), 8.05 (d, J=5.0 Hz,1H), 7.99 (d, J=9.0 Hz, 1H), 7.72 (s, 1H), 5.01-4.94 (m, 1H), 2.91 (s,3H), 1.31 (d, J=7.0 Hz, 3H). LC-MS m/z: 418.0 [M+H]⁺. HPLC: Purity (214nm): 98%; t_(R)=7.79 min.

(R)-7-Methyl-5-(5-(trifluoromethyl)pyridin-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.23 mmol) and 5-(trifluoromethyl)pyridin-3-ylboronic acidafforded the title compound (59 mg, 61%) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆) δ 9.72 (d, J=1.6 Hz, 1H), 9.21 (d, J=3.2 Hz, 1H), 8.95 (s,1H), 8.73 (s, 1H), 8.42 (d, J=9.2 Hz, 1H), 8.21 (s, 1H), 5.02-4.96 (m,1H), 2.90 (s, 3H), 1.44 (d, J=7.2 Hz, 3H). LC-MS m/z: 418.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=8.49 min.

(S)-7-Methyl-5-(5-(trifluoromethyl)pyridin-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.23 mmol) and 5-(trifluoromethyl)pyridin-3-ylboronic acidafforded the title compound (33.4 mg, 34%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 9.72 (d, J=1.6 Hz, 1H), 9.21 (d, J=3.2 Hz, 1H),8.95 (s, 1H), 8.73 (s, 1H), 8.42 (d, J=9.2 Hz, 1H), 8.21 (s, 1H),5.02-4.96 (m, 1H), 2.90 (s, 3H), 1.44 (d, J=7.2 Hz, 3H). LC-MS m/z:418.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.48 min.

7-Methyl-5-(6-(trifluoromethyl)pyridin-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and 6-(trifluoromethyl)pyridin-3-ylboronic acidafforded the title compound (18 mg, 19%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆) δ 9.57 (s, 1H), 8.85 (dd, J=8.5 Hz, 1.5 Hz, 1H), 8.75 (s,1H), 8.36 (d, J=9.0 Hz, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.12 (s, 1H),5.02-4.94 (m, 1H), 2.90 (s, 3H), 1.47 (d, J=7.0 Hz, 3H). LC-MS m/z:418.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.66 min.

5-(Benzo[d][1,3]dioxol-5-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(140 mg, 0.46 mmol) and2-(benzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneafforded the title compound (35 mg, 19%) as a white solid. ¹H NMR (500MHz, MeOD-d₄) δ 8.58 (s, 1H), 7.82 (dd, J=8.0 Hz, 1.5 Hz 1H), 7.20 (d,J=1.5 Hz, 1H), 7.66 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.12 (s, 1H),4.99-4.96 (m, 1H), 2.90 (s, 3H), 1.54 (d, J=7.0 Hz, 3H). LC-MS m/z:393.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=8.49 min.

(S)-5-(5-Chloropyridin-3-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(150 mg, 0.54 mmol) and 5-chloropyridin-3-ylboronic acid afforded thetitle compound (37 mg, 19%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.41 (s, 1H), 8.85 (s, 1H), 8.72 (s, 1H), 8.62 (s, 1H), 8.07(d, J=8.0 Hz, 1H), 8.06 (s, 1H), 3.65-3.60 (m, 1H), 2.86 (s, 3H), 1.28(d, J=6.5 Hz, 3H), 1.14-1.10 (m, 1H), 0.56-0.46 (m, 2H), 0.42-0.32 (m,2H). LC-MS m/z: 356.1 [M+H]⁺. HPLC: Purity (214 nm): 99%; t_(R)=8.16min.

(R)-5-(5-Chloropyridin-3-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.25 mmol) and 5-chloropyridin-3-ylboronic acid afforded thetitle compound (21 mg, 22%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆)δ 9.42 (d, J=1.6 Hz, 1H), 8.85 (d, J=2.0 Hz, 1H), 8.73 (s, 1H) 8.62 (s,1H), 8.09 (s, 1H), 8.08 (d, J=7.6 Hz, 1H), 4.66-4.58 (m, 1H), 2.87 (s,3H), 1.28 (d, J=6.4 Hz, 3H), 1.16-1.07 (m, 1H), 0.58-0.46 (m, 2H),0.44-0.29 (m, 2H). LC-MS m/z: 356.1 [M+H]⁺. HPLC: Purity (214 nm): 95%;t_(R)=8.21 min.

5-(5-Chloropyridin-3-yl)-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(150 mg, 0.54 mmol) and 5-chloropyridin-3-ylboronic acid afforded thetitle compound (37 mg, 19%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.39 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.5 Hz, 1H), 8.69 (t,J=2.0 Hz, 1H), 8.58 (s, 1H), 8.07 (s, 1H), 8.04 (s, 1H), 2.86 (s, 3H),1.40-1.38 (m, 1H), 1.38 (s, 6H), 0.53-0.48 (m, 4H).

N-((1R,4R)-4-Butoxycyclohexyl)-5-(5-chloropyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (600 mg,2.84 mg) and (1R,4R)-4-butoxycyclohexanamine affordedN-((1R,4R)-4-butoxycyclohexyl)-5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(820 mg, 80%) as a yellow solid. LC-MS m/z: 365.2 [M+H]⁺. Purity (214nm): 63.1%; t_(R)=1.96 min.

Following general procedure D,N-((1R,4R)-4-butoxycyclohexyl)-5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(150 mg, 0.41 mmol) and 5-chloropyridin-3-ylboronic acid afforded thetitle compound (35 mg, 19%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.36 (s, 1H), 8.85 (s, 1H), 8.69 (s, 1H), 8.62 (s, 1H), 8.03(s, 1H), 7.99 (d, J=6.5 Hz, 1H), 3.85-3.83 (m, 1H), 3.44-3.41 (m, 1H),3.41 (t, J=6.0 Hz, 2H), 2.85 (s, 3H), 2.02-1.97 (m, 4H), 1.48-1.32 (m,8H), 0.89 (t, J=6.0 Hz, 3H). LC-MS m/z: 442.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=9.42 min.

5-(7-Fluorobenzo[d][1,3]dioxol-5-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 3-fluoro-2-hydroxybenzaldehyde (5 g, 35.6 mmol) in MeCN(40 mL) was added NBS (6.008 g, 36 mmol) and CH₃CO₂NH₄ (270 mg, 3.56mmol) at RT and the mixture was stirred at RT for 2 h, poured into H₂O(30 mL) and extracted with EA (20 mL×2). The organic layers were driedover anhydrous Na₂SO₄, filtered, concentrated in vacuo, and the residuepurified by silica gel column chromatography (PE/EA=8/1 to 4/1) toafford 5-bromo-3-fluoro-2-hydroxybenzaldehyde (6.6 g, 85%) as a yellowsolid. ¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H), 10.22 (s, 1H), 7.84(dd, J=10.4 Hz, 2.4 Hz, 1H), 7.59 (dd, J=2.4 Hz, 1.6 Hz, 1H). LC-MS:t_(R)=1.284 min.

To a solution of 5-bromo-3-fluoro-2-hydroxybenzaldehyde (6.6 g, 30.13mmol) in THF (43 mL) was added dropwise aqueous NaOH solution (0.05N,119 mL, 6 mmol) at 0° C., followed by the addition of 30% H₂O₂ solution(16.5 mL). The mixture was stirred for 2 h at RT, followed by theaddition of a second portion of 30% H₂O₂ solution (16.5 mL). Afterstirring for 4 h, it was cooled to 0° C. and aq. NaOH solution (2N, 18.5mL) was added until pH 10˜11 was reached, and then the mixture wasstirred for 0.5 hour and quenched with cone. HCl at 0° C. to pH 2-3. Itwas extracted with DCM (40 mL×3), and the organic phases were washedwith brine (50 mL×2), dried over anhydrous Na₂SO₄, and filtered. Thefiltrate was concentrated in vacuo to afford5-bromo-3-fluorobenzene-1,2-diol (5.1 g, 82%) as a yellow oil. LC-MSm/z: 205 [M−H]⁻. t_(R)=1.469 min.

To a solution of 5-bromo-3-fluorobenzene-1,2-diol (5.0 g, 18.5 mmol) andBrClCH₂ (3.6 g, 27.75 mmol) in anhydrous DMF (100 mL) was added Cs₂CO₃(12.1 g, 37 mmol). The mixture was stirred at 60° C. for 3 h, pouredinto H₂O (200 mL), and extracted with EA (80 mL×3). The combinedextracts were washed with brine (100 mL), dried over anhydrous Na₂SO₄,and filtered. The filtrate was concentrated in vacuo, and the residuewas purified by silica gel column chromatography (PE/EA=50/1 to 10/1) toafford 6-bromo-4-fluorobenzo[d][1,3]dioxole (1.8 g, 43%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 6.13 (s, 1H), 6.08 (s, 1H), 5.26 (s,2H). LC-MS m/z: t_(R)=1.89 min.

To a solution of 6-bromo-4-fluorobenzo[d][1,3]dioxole (1.6 g, 7.3 mmol)in dioxane (20 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.04 g,8.03 mmol), AcOK (1.43 g, 14.6 mmol) and Pd(dppf)Cl₂.DCM (534 mg, 0.73mmol) under N₂. The mixture was stirred at 110° C. for 14 h, poured intoH₂O (60 mL) and extracted with EA (50 mL×2). The organic layers weredried over anhydrous Na₂SO₄, and filtered. The filtrate was concentratedin vacuo, and the residue was purified by silica gel columnchromatography (PE/EA=30/1 to 10/1) to afford2-(7-fluorobenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(1.6 g, 82%) as yellow oil. LC-MS: t_(R)=2.03 min.

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.37 mmol) and2-(7-fluorobenzo[d][1,3]dioxol-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneafforded the title compound (5.8 mg, 4%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.44 (d, J=9.0 Hz, 1H), 7.94 (s, 1H), 7.82(dd, J=11.5 Hz, 1.0 Hz, 1H), 7.70 (d, J=1.0 Hz, 1H), 6.29 (s, 2H),5.00-4.92 (m, 1H), 2.83 (s, 3H), 1.44 (d, J=7.0 Hz, 3H). LC-MS m/z:411.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.71 min.

(R)-5-(7-Fluorobenzo[d]oxazol-5-yl)-7-methyl-N-(1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a mixture of 2-amino-4-bromo-6-fluorophenol (500 mg, 2.4 mmol) inmethyl orthoformate (5 mL) was added p-TsOH-H₂O (41.6 mg, 0.24 mmol).The mixture was stirred for 2 hours at 85° C. under N₂, and concentratedin vacuo. The residue was purified by silica gel chromatography(PE/EA=20/1-10/1) to afford 5-bromo-7-fluorobenzo[d]oxazole (370 mg,67%) as a yellow oil. ¹H NMR (500 MHz, DMSO-d₆): δ 8.93 (s, 1H), 7.96(s, 1H), 8.78 (d, J=10.0 Hz, 1H).

A mixture of 5-bromo-7-fluorobenzo[d]oxazole (90 mg, 0.41 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (157 mg,0.62 mmol), Pd(PPh₃)₂Cl₂ (33 mg, 0.04 mmol) and KOAc (81 mg, 0.83 mmol)in 1,4-dioxane (5 mL) was stirred for 2 h at 90° C. under N₂, and thencooled to RT. To this mixture was added(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(78 mg, 0.25 mmol), Na₂CO₃ (88 mg, 0.83 mmol) and H₂O (1 mL) and stirredfor 3 h at 90° C. under N₂. The mixture was diluted with H₂O (10 mL),extracted with EA (15 mL×3), washed with brine (10 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo,and the residue was purified by silica gel column chromatography(PE:EA=10:1˜1:1) and preparative HPLC (MeCN/NH₄HCO₃) to afford the titlecompound (25 mg, 38%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.02 (s, 1H), 8.68 (s, 1H), 8.60 (d, J=1.6 Hz, 1H), 8.49 (d, J=9.6 Hz,1H), 8.27 (d, J=12.4 Hz, 1H), 8.14 (s, 1H), 5.00˜4.98 (m, 1H), 2.87 (s,3H), 1.47 (d, J=7.2 Hz, 3H). LC-MS m/z: 408.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.34 min.

(S)-5-(7-Fluorobenzo[d]oxazol-5-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 5-bromo-7-fluorobenzo[d]oxazole (90 mg, 0.41 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (157 mg,0.62 mmol), Pd(PPh₃)₂Cl₂ (33 mg, 0.04 mmol) and KOAc (81 mg, 0.83 mmol)in 1,4-dioxane (5 mL) was stirred for 2 h at 90° C. under N₂, and thencooled to RT. To this mixture were added(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(78 mg, 0.25 mmol), Na₂CO₃ (88 mg, 0.83 mmol) and water (1 mL) andstirred for 3 h at 90° C. under N₂. The mixture was diluted with H₂O (10mL), extracted with EA (15 mL×3), washed with brine (10 mL), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo,and the residue was purified by silica gel column chromatography(PE:EA=10:1˜1:1) and preparative HPLC (MeCN/NH₄HCO₃) to afford the titlecompound (50 mg, 75%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ9.02 (s, 1H), 8.68 (s, 1H), 8.60 (d, J=1.6 Hz, 1H), 8.49 (d, J=9.6 Hz,1H), 8.27 (d, J=12.4 Hz, 1H), 8.14 (s, 1H), 5.00˜4.98 (m, 1H), 2.87 (s,3H), 1.47 (d, J=7.2 Hz, 3H). LC-MS m/z: 408.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.34 min.

5-(3-Fluoro-4-(2-methoxyethoxy)phenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,4-bromo-2-fluoro-1-(2-methoxyethoxy)benzene (4.0 g, 16.0 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) afforded2-(3-fluoro-4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(4.0 g, 83%) as a yellow solid. LC-MS m/z: 314.3 [M+H]⁺. Purity (214nm): 73%; t_(R)=1.98 min.

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(174 mg, 0.81 mmol) and2-(3-fluoro-4-(2-methoxyethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneafforded the title compound (96 mg, 43%) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 8.62 (s, 1H), 8.47 (d, J=9.2 Hz, 1H), 8.08 (d, J=10.8Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.93 (s, 1H), 7.44 (t, J=8.8 Hz, 1H),5.01-4.96 (m, 1H), 4.32 (t, J=3.6 Hz, 2H), 3.73 (t, J=3.6 Hz, 2H), 2.84(s, 3H), 1.46 (d, J=6.8 Hz, 3H). LC-MS m/z: 441.1 [M+H]⁺. HPLC: Purity(214 nm): >99%; t_(R)=8.58 min.

5-(3-Fluoro-4-morpholinophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.23 mmol) and 3-fluoro-4-morpholinophenylboronic acid affordedthe title compound (48 mg, 47%) as a yellow solid. 1H NMR (500 MHz,MeOD-d₄) δ 8.59 (s, 1H), 8.01 (d, J=8.5 Hz, 1H), 7.96 (dd, J=14.5 Hz,1.5 Hz, 1H), 7.70 (s, 1H), 7.21 (t, J=8.0 Hz, 1H), 4.99-4.95 (m, 1H),3.89 (t, J=5.0 Hz, 4H), 3.26 (dd, J=9.5 Hz, 4.5 Hz, 4H), 2.91 (s, 3H)1.54 (d, J=6.5 Hz, 3H). LC-MS m/z: 452.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.72 min.

(S)-5-(3-Cyanothiophen-2-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.29 mmol) and 2-bromothiophene-3-carbonitrile afforded thetitle compound (5.5 mg, 5%) as a yellow solid. ¹H NMR (400 MHz,DMSO-d₆): δ 8.64 (s, 1H), 8.13 (d, J=5.2 Hz, 1H), 7.89 (d, J=8.0 Hz,1H), 7.75 (d, J=4.4 Hz, 1H), 7.70 (s, 1H), 3.55-3.53 (m, 1H), 2.87 (s,3H), 1.30 (d, J=6.4 Hz, 3H), 1.20-1.11 (m, 1H), 0.49-0.48 (m, 1H),0.43-0.41 (m, 1H), 0.31-0.23 (m, 2H). LC-MS m/z: 352.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.17 min.

(R)-5-(3-Cyanothiophen-2-yl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(R)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(160 mg, 0.58 mmol) and 2-bromothiophene-3-carbonitrile afforded thetitle compound (53 mg, 26%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄)δ 8.62 (s, 1H), 8.24 (d, J=6.5 Hz, 1H), 7.93 (d, J=5.0 Hz, 1H), 7.66 (s,1H), 7.58 (d, J=5.0 Hz, 1H), 3.63-3.58 (m, 1H), 2.93 (s, 3H), 1.43 (d,J=7.0 Hz, 3H), 1.27-1.24 (m, 1H), 0.60-0.56 (m, 1H), 0.52-0.47 (m, 1H),0.44-0.41 (m, 1H), 0.33-0.28 (m, 1H). LC-MS m/z: 352.0 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.51 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(1-methyl-1H-benzo[d]imidazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 4-bromo-1-fluoro-2-nitrobenzene (2.0 g, 9.1 mmol) inCH₃NH₂/MeOH (10 mL) was heated at 80° C. for 2 h in a sealed tube,poured into H₂O (60 mL) and extracted with EA (40 mL×2). The organiclayers were dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to afford 4-bromo-N-methyl-2-nitroaniline (2.1 g, 100%) as ayellow solid. LC-MS m/z: 232.9 [M+H]⁺. t_(R)=1.90 min.

To a solution of 4-bromo-N-methyl-2-nitroaniline (2.1 g, 9 mmol) in MeOH(50 mL) was added Fe powder (2.5 g, 45 mmol) and NH₄Cl (4.8 g, 90 mmol).The mixture was stirred at 80° C. for 4 h, poured into H₂O (60 mL) andextracted with EA (40 mL×2). The organic layers were dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to afford4-bromo-N¹-methylbenzene-1,2-diamine (2.0 g, 99%) as a yellow solid.LC-MS m/z: 203.1 [M+H]⁺. t_(R)=1.64 min.

To a solution of 4-bromo-N¹-methylbenzene-1,2-diamine (1.7 g, 8 mmol) intriethyl orthoformate (10 mL) was added PTSA.H₂O (152 mg, 0.8 mmol). Themixture was stirred at 85° C. for 2 h, poured into H₂O (50 mL) andextracted with EA (40 mL×2). The organic layers were dried overanhydrous Na₂SO₄, filtered, concentrated in vacuo, and purified bysilica gel column chromatography (PE/EA=50/1 to 10/1) to afford5-bromo-1-methyl-1H-benzo[d]imidazole (1.5 g, 89%) as a yellow solid.LC-MS m/z: 211.1 [M+H]⁺. t_(R)=1.90 min.

To a solution of 5-bromo-1-methyl-1H-benzo[d]imidazole (1.0 g, 4.74mmol) in dioxane (10 mL) were added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.5 g, 5.68mmol), sodium 2-ethylhexanoate (1.968 g, 11.86 mmol) and Pd(dppf)Cl₂.DCM(247 mg, 0.474 mmol) under N₂. The mixture was stirred at 110° C. for 4h, poured into H₂O (60 mL) and extracted with EA (50 mL×2). The organiclayers were dried over anhydrous Na₂SO₄, filtered, concentrated invacuo, and purified by silica gel column chromatography (PE/EA=1/1) toafford1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole(1.0 g, 82%) as a yellow solid. LC-MS m/z: 259.1 [M+H]⁺. t_(R)=1.67 min.

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(150 mg, 0.45 mmol) and1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazoleafforded the title compound (19 mg, 10%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.72 (d, J=9.5 Hz, 1H), 8.62 (s, 1H), 8.61 (d, J=9.0 Hz,1H), 8.34 (s, 1H), 8.23 (d, J=8.5 Hz, 1H), 8.08 (s, 1H), 7.83 (d, J=8.5Hz, 1H), 4.55-4.51 (m, 1H), 3.92 (s, 3H), 2.86 (s, 3H), 1.31-1.27 (m,1H), 0.72-0.62 (m, 1H), 0.61-0.58 (m, 2H), 0.44-0.40 (m, 1H). LC-MS m/z:429.1 [M+H]⁺. HPLC Purity (214 nm): 93.56%; t_(R)=7.55 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 4-bromo-2-fluoro-1-nitrobenzene (4.0 g, 18.26 mmol) in 30mL MeNH₂/MeOH was stirred at 80° C. for 15 h, and poured into H₂O (100mL). The mixture was extracted with EA (30 mL×3), dried over anhydrousNa₂SO₄, and filtered. The filtrate was concentrated in vacuo to afford5-bromo-N-methyl-2-nitroaniline (3.8 g, 90%) as a yellow solid. LC-MSm/z: 232.9 [M+H]⁺. Purity (214 nm): 88.0%; t_(R)=1.89 min.

To a mixture of 5-bromo-N-methyl-2-nitroaniline (3.6 g, 16 mmol) in 100mL of MeOH were added Fe powder (4.38 g, 78 mmol) and NH₄Cl (16.53 g,311.8 mmol) at RT and the mixture was stirred at 75° C. for 15 h, cooledand filtered. The filtrate was concentrated in vacuo, and the residuewas washed with H₂O (50 mL). The aqueous phase was extracted with EA (30mL×3), and the organic phases were dried over anhydrous Na₂SO₄, andfiltered. The filtrate was concentrated in vacuo to afford5-bromo-N¹-methylbenzene-1,2-diamine as a black solid (3.1 g, 90%).LC-MS m/z: 201.1 [M+H]⁺. Purity (214 nm): 73%; t_(R)=1.66 min.

To a mixture of 5-bromo-N¹-methylbenzene-1,2-diamine (2.0 g, 10.0 mmol)in 15 mL of trimethoxymethane was added p-TsOH.H₂O (0.172 g, 0.02 mmol)at RT and the mixture was stirred at 105° C. for 1 h, cooled andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (20.0 g, PE/EA: 10/1-5/1) to afford6-bromo-1-methyl-1H-benzo[d]imidazole as a yellow solid (1.6 g, 76%).LC-MS m/z: 213.0 [M+H]⁺. Purity (214 nm): 99%; t_(R)=1.57 min.

Following general procedure E*,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(160 mg, 0.48 mmol) and 6-bromo-1-methyl-1H-benzo[d]imidazole affordedthe title compound (22 mg, 11%) as a yellow solid. ¹H NMR (500 MHz,CDCl₃): δ 8.70 (d, J=9.0 Hz, 1H), 8.64 (s, 1H), 8.50 (s, 1H), 8.39 (s,1H), 8.16 (dd, J=8.5 Hz, 1.5 Hz, 1H), 8.07 (s, 1H), 7.85 (d, J=8.5 Hz,1H), 4.56-4.52 (m, 1H), 3.94 (s, 3H), 2.89 (s, 3H), 1.36-1.32 (m, 1H),0.73-0.68 (m, 1H), 0.64-0.56 (m, 2H), 0.46-0.42 (m, 1H). LC-MS m/z:429.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.44 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, 6-bromo-1-methyl-1H-benzo[d]imidazole(500 mg, 2.38 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) afforded1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole(300 mg, 49%) as a yellow solid. LC-MS m/z: 441.0 [M+H]⁺; Purity (214nm): 86.74%; t_(R)=1.68 min.

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazoleafforded the title compound (45 mg, 46%) as a yellow solid. ¹H NMR (400MHz, DMSO-d₆): δ 8.70 (d, J=9.6 Hz, 1H), 8.63 (s, 1H), 8.49 (d, J=1.2Hz, 1H), 8.38 (s, 1H), 8.15 (dd, J=8.8 Hz, 2.0 Hz, 1H), 8.06 (s, 1H),7.85 (d, J=8.8 Hz, 1H), 4.54-4.48 (m, 1H), 3.93 (s, 3H), 2.87 (s, 3H),1.35-1.30 (m, 1H), 0.72-0.65 (m, 1H), 0.63-0.55 (m, 2H), 0.44-0.40 (m,1H). LC-MS m/z: 429.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.42min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(1-methyl-1H-benzo[d]imidazol-6-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.33 mmol) and 6-bromo-1-methyl-1H-benzo[d]imidazole affordedthe title compound (6 mg, 5%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 8.70 (d, J=9.5 Hz, 1H), 8.64 (s, 1H), 8.50 (d, J=1.5 Hz,1H), 8.40 (s, 1H), 8.16 (dd, J=8.5 Hz, 1.5 Hz, 1H), 8.07 (s, 1H), 7.85(d, J=8.5 Hz, 1H), 4.54-4.48 (m, 1H), 3.93 (s, 3H), 2.87 (s, 3H),1.35-1.30 (m, 1H), 0.72-0.65 (m, 1H), 0.63-0.55 (m, 2H), 0.44-0.40 (m,1H). LC-MS m/z: 429.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.46min.

5-(1H-Benzo[d]imidazol-6-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 6-bromo-1H-benzo[d]imidazole (1 g, 5.08 mmol), Boc₂O (1.56g, 4.22 mmol), and DIPEA (1.54 g, 15.23 mmol) in DCM (20 mL) was stirredat 20° C. for 16 h under N₂, and concentrated in vacuo. The residue waspurified by flash chromatography on silica gel (EA:PE; 0 to 10%) toafford tert-butyl 6-bromo-1H-benzo[d]imidazole-1-carboxylate (1.4 g,92%) as a yellow solid. LC-MS m/z: 241.0 [M-56]⁺. LC-MS Purity (214nm): >98%; t_(R)=1.98 min.

The mixture of tert-butyl 6-bromo-1H-benzo[d]imidazole-1-carboxylate(1.4 g, 4.74 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.44 g,5.65 mmol), Pd(dppf)Cl₂.DCM (383 mg, 0.47 mmol), and CH₃COOK (1.16 g,11.78 mmol) in 1,4-dioxane (10 mL) was stirred at 70° C. for 16 h underN₂. The mixture was filtered and the organic layers were dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give crudetert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate,which was used in the next step directly (4 g). LC-MS m/z: 289.1[M-56]⁺. LC-MS Purity (214 nm): >47%; t_(R)=2.07 min.

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and tert-butyl6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylateafforded the title compound (6 mg, 5%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆): δ 12.79 (s, 1H), 8.70 (d, J=9.5 Hz, 1H), 8.61 (s, 1H),8.47 (s, 1H), 8.12 (d, J=9 Hz, 1H), 8.03 (s, 1H), 7.76 (s, 1H),4.50-4.45 (m, 1H), 2.97 (s, 3H), 1.32-1.28 (m, 1H), 0.73-0.68 (m, 1H),0.64-0.60 (m, 2H), 0.45-0.40 (m, 1H). LC-MS m/z: 415.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=7.03 min.

5-(1H-Benzo[d]imidazol-7-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

The mixture of 7-bromo-1H-benzo[d]imidazole (1 g, 5.08 mmol), Boc₂O(1.56 g, 4.22 mmol), and DIPEA (1.54 g, 15.23 mmol) in DCM (20 mL) wasstirred at 20° C. for 16 h under N₂, and concentrated in vacuo. Theresidue was purified by flash chromatography on silica gel (EA:PE; 0 to10%) to afford tert-butyl 7-bromo-1H-benzo[d]imidazole-1-carboxylate(1.2 g, 79%) as a yellow solid. LC-MS m/z: 241.0 [M-56]⁺. LC-MS Purity(214 nm): >98%; t_(R)=1.93 min.

The mixture of tert-butyl 7-bromo-1H-benzo[d]imidazole-1-carboxylate(1.2 g, 4.04 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.23 g,4.85 mmol), Pd(dppf)Cl₂.DCM (329 mg, 0.40 mmol), and CH₃COOK (0.99 g,10.10 mmol) in 1,4-dioxane (10 mL) was stirred at 70° C. for 16 h underN₂. The mixture was filtered and the organic layers were dried overanhydrous MgSO₄, filtered and concentrated in vacuo to give crudetert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylate,which was used in the next step directly (3 g). LC-MS m/z: 289.1[M-56]⁺. LC-MS Purity (214 nm): >42%; t_(R)=2.07 min.

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and tert-butyl7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole-1-carboxylateafforded the title compound (6 mg, 5%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆): δ 12.89 (s, 1H), 8.82 (d, J=9.5 Hz, 1H), 8.70 (s, 1H),8.48 (s, 1H), 8.16 (d, J=5.5 Hz, 1H), 7.84 (s, 1H), 7.44 (d, J=8.0 Hz,1H), 4.50-4.42 (m, 1H), 2.90 (s, 3H), 1.34-1.27 (m, 1H), 0.72-0.67 (m,1H), 0.60-0.58 (m, 2H), 0.44-0.38 (m, 1H). LC-MS m/z: 415.1 [M+H]⁺. HPLCPurity (214 nm): 99%; t_(R)=7.54 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(1-methyl-1H-benzo[d]imidazol-7-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 1-bromo-2-fluoro-3-nitrobenzene (2.19 g, 10.0 mmol) inMeNH₂ (MeOH solution, 40 mL) was stirred at reflux for 3 h, poured intosaturated NaHCO₃ aqueous solution (100 mL), and extracted with EA (80mL×3). The combined organic phases were dried over anhydrous Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo to afford2-bromo-N-methyl-6-nitroaniline (1.9 g, 82.6% yield) as a red oil. LC-MSm/z: 231.0 [M+H]⁺. t_(R)=1.82 min.

A mixture of 2-bromo-N-methyl-6-nitroaniline (1.9 g, 8.26 mmol), Fepowder (2.8 g), and NH₄Cl (8.84 g, 165.2 mmol) in MeOH (100 mL) wasstirred at reflux for 8 h, and filtered. The filtrate was concentratedin vacuo, and the residue was dissolved in saturated NaHCO₃ solution(200 mL). The mixture was extracted with EA (150 mL×3). The combinedextracts were dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to afford a mixture of6-bromo-N¹-methylbenzene-1,2-diamine and7-bromo-1-methyl-1H-benzo[d]imidazole (1.8 g) as a green oil. LC-MS m/z:211.0 [M+H]⁺. t_(R)=1.56 min. 201.0 [M+H]⁺. t_(R)=1.64 min.

A mixture of 6-bromo-N¹-methylbenzene-1,2-diamine and7-bromo-1-methyl-1H-benzo[d]imidazole (1.8 g, crude), trimethoxymethane(10 mL) and 4-methylbenzenesulfonic acid (172 mg, 1.0 mmol) was stirredat 85° C. for 1 h, and concentrated in vacuo. The residue was purifiedby silica gel column chromatography (EA/PE=4/1) to afford7-bromo-1-methyl-1H-benzo[d]imidazole (1.6 g, 92% yield over 2 steps) asa green solid. LC-MS m/z: 213.1 [M+H]⁺. t_(R)=1.58 min.

Following general procedure D, 7-bromo-1-methyl-1H-benzo[d]imidazole(105 mg, 0.5 mmol) and4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) affordedcrude1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole(650 mg) as a black oil, which was used in the next step without furtherpurification. LC-MS m/z: 259.2 [M+H]⁺. t_(R)=1.74 min.

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.21 mmol) and1-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazoleafforded the title compound (68 mg, 59%) as a grey solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.74 (s, 1H), 8.34 (d, J=9.5 Hz, 1H), 8.33 (s, 1H),7.88 (d, J=8.0 Hz, 1H), 7.70 (s, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.40 (t,J=7.5 Hz, 1H), 4.38-4.33 (m, 1H), 3.67 (s, 3H), 2.90 (s, 3H), 1.05-1.00(m, 1H), 0.63-0.44 (m, 3H), 0.26-0.21 (m, 1H). LC-MS m/z: 429.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=7.43 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(1-methyl-1H-benzo[d]imidazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and 4-bromo-1-methyl-1H-benzo[d]imidazole affordedthe title compound (60 mg, 29%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃): δ 8.84 (d, J=10.0 Hz, 1H), 8.75 (s, 1H), 8.70 (s, 1H), 8.30 (d,J=7.5 Hz, 1H), 8.05 (s, 1H), 7.63 (d, J=8.0 Hz, 1H), 7.55 (t, J=7.5 Hz,1H), 4.60-4.56 (m, 1H), 3.97 (s, 3H), 2.97 (s, 3H), 1.28-1.25 (m, 1H),0.74-0.70 (m, 1H), 0.63-0.56 (m, 3H). LC-MS m/z: 429.1 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=8.27 min.

5-(1H-Benzo[d]imidazol-2-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a mixture of ethyl5-formyl-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (235 mg, 1.01mmol) and benzene-1,2-diamine (109 mg, 1.01 mmol) in MeCN (6 mL) wereadded 30% (w/w) H₂O₂(241 mg, 7.09 mmol), and 37% (w/w) HCl (130 mg, 3.61mmol). The mixture was stirred at RT for 2 h, diluted with H₂O (100 mL)and extracted with DCM (30 mL×3). The organic phases were dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo,and the residue was purified by silica gel column chromatography (40 g,eluting with PE/EA=I/O to 1/4) to afford ethyl5-(1H-benzo[d]imidazol-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylateas a grey solid (102 mg, 31%). LC-MS m/z: 322.1 [M+H]⁺. t_(R)=1.71 min.

Following general procedure B*, ethyl5-(1H-benzo[d]imidazol-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(97 mg, 0.3 mmol) afforded5-(1H-benzo[d]imidazol-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (86 mg, 92%) as a light yellow solid. LC-MS m/z: 294.1 [M+H]⁺.t_(R)=1.25 min.

Following general procedure A,5-(1H-benzo[d]imidazol-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (81 mg, 0.28 mmol) and 1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (20 mg, 18%) as a white solid.¹H NMR (500 MHz, DMSO-d₆) δ 13.43 (s, 1H), 8.75 (s, 1H), 8.41 (d, J=9.0Hz, 1H), 8.12 (s, 1H), 7.86-7.68 (m, 2H), 7.42-7.29 (m, 2H), 4.26-4.17(m, 1H), 2.91 (s, 3H), 1.71-1.63 (m, 1H), 0.81-0.76 (m, 1H), 0.70-0.59(m, 2H), 0.43-0.38 (m, 1H). LC-MS m/z: 415.1 [M+H]⁺. HPLC: Purity (214nm): 97%; t_(R)=8.15 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(1-methyl-1H-benzo[d]imidazol-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.178 mmol) and 2-bromo-1-methyl-1H-benzo[d]imidazole affordedthe title compound (19 mg, 25%) as a white solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.75 (s, 1H), 8.28 (d, J=9.0 Hz, 1H), 8.18 (s, 1H), 7.81 (d,J=7.5 Hz, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.35 (t,J=7.5 Hz, 1H), 4.39 (s, 3H), 4.33-4.27 (m, 1H), 2.91 (s, 3H), 1.30-1.25(m, 1H), 0.76-0.67 (m, 2H), 0.62-0.57 (m, 1H), 0.39-0.32 (m, 1H). LC-MSm/z: 429.1 [M+H]⁺. HPLC Purity (214 nm): 93.8%; t_(R)=8.79 min.

5-(5-i-Propyl-2-oxooxazolidin-3-yl)-7-methyl-N-(2,2,2-trifluoro-1-phenylethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylic acid (400 mg,1.89 mmol) and 2,2,2-trifluoro-1-phenylethanamine afforded5-chloro-7-methyl-N-(2,2,2-trifluoro-1-phenylethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(558 mg, 80%) as a white solid. LC-MS m/z: 369.0 [M+H]⁺. LCMS:t_(R)=1.92 min.

Following general procedure H,5-chloro-7-methyl-N-(2,2,2-trifluoro-1-phenylethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.54 mmol) and 5-iso-propyloxazolidin-2-one afforded the titlecompound (15 mg, 6%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄) δ 8.50(s, 1H), 8.09 (dd, J=5.5 Hz, 1.0 Hz, 1H), 7.60-7.54 (m, 2H), 7.49-7.44(m, 3H), 6.00-5.98 (m, 1H), 4.60-4.55 (m, 1H), 4.50-4.44 (m, 1H), 4.09(dd, J=10.0 Hz, 8.0 Hz, 1H), 2.84 (s, 3H), 2.11-2.03 (m, 1H), 1.12 (dd,J=6.5 Hz, 6.0 Hz, 3H), 1.04 (dd, J=6.5 Hz, 2.5 Hz, 3H). LC-MS m/z: 462.1[M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=9.12 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-((S)-2-oxo-5-phenyloxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide&N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-((R)-2-oxo-5-phenyloxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

The solution of5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.6 mmol), 2-amino-1-phenylethanol (495 mg, 3.61 mmol) and TEA(60 mg, 0.60 mmol) in MeCN (2 mL) was stirred at 80° C. for 2 h, andcooled. The solution was concentrated in vacuo and the residue waspurified by silica gel column chromatography (EA) to affordN-(1-cyclopropyl-2,2,2-trifluoroethyl)-5-(2-hydroxy-2-phenylethylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(250 mg, 96%) as a white solid. LC-MS m/z: 434.1 [M+H]⁺. Purity (214nm): >97%; t_(R)=1.71 min.

A solution ofN-(1-cyclopropyl-2,2,2-trifluoroethyl)-5-(2-hydroxy-2-phenylethylamino)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(200 mg, 0.46 mmol), CDI (1.12 g, 6.32 mmol) and TEA (93 mg, 0.92 mmol)in THF (8 mL) was stirred at 70° C. for 16 hours, and cooled. Thesolution was concentrated in vacuo and the residue was purified bysilica gel column chromatography (50% EA in PE) and triturated with Et₂Oto affordN-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-((S)-2-oxo-5-phenyloxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(48 mg, 23%) as a white solid andN-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-((R)-2-oxo-5-phenyloxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(56 mg, 26%) as a white solid.

N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-((S)-2-oxo-5-phenyloxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide:¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.05 (d, J=9.5 Hz, 1H), 7.97(s, 1H), 7.56-7.55 (m, 2H), 7.49-7.42 (m, 3H), 5.92 (t, J=8.0 Hz, 1H),4.68 (t, J=9.0 Hz, 1H), 4.37-4.33 (m, 1H), 4.24-4.20 (m, 1H), 2.82 (s,3H), 1.19-1.12 (m, 1H), 0.62-0.57 (m, 1H), 0.52-0.47 (m, 1H), 0.41-0.32(m, 1H), 0.31-0.27 (m, 1H). LC-MS m/z: 460.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.76 min.

N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-((R)-2-oxo-5-phenyloxazolidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide:¹H NMR (500 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.98(s, 1H), 7.56-7.55 (m, 2H), 7.50-7.43 (m, 3H), 5.90 (t, J=8.5 Hz, 1H),4.78 (t, J=10.0 Hz, 1H), 4.34-4.31 (m, 1H), 4.14-4.11 (m, 1H), 2.82 (s,3H), 1.25-1.17 (m, 1H), 0.67-0.62 (m, 1H), 0.56-0.52 (m, 2H), 0.36-0.32(m, 1H). LC-MS m/z: 460.1 [M+H]⁺. HPLC: Purity (214 nm): >97%;t_(R)=8.72 min.

N—((R)-1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-iso-propyl-2-oxooxazolidin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.21 mmol) and 5-iso-propyloxazolidin-2-one afforded the titlecompound (13 mg, 14%) as a white solid. 1H NMR (500 MHz, MeOD-d₄) δ 8.51(s, 1H), 8.07 (d, J=6.5 Hz, 1H), 4.56-4.52 (m, 1H), 4.47-4.37 (m, 2H),4.09-4.01 (m, 1H), 2.86 (s, 3H), 1.27-1.25 (m, 1H), 1.12 (dd, J=6.5 Hz,3.0 Hz, 3H), 1.04 (dd, J=6.5 Hz, 2.0 Hz, 3H), 0.78-0.75 (m, 1H),0.65-0.60 (m, 1H), 0.59-0.50 (m, 2H). LC-MS m/z: 426.1 [M+H]⁺. HPLC:Purity (254 nm): >99%; t_(R)=8.91 min.

N—((S)-1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-iso-propyl-2-oxooxazolidin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.21 mmol) and 5-iso-propyloxazolidin-2-one afforded the titlecompound (5.6 mg, 6%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄) δ 8.51(s, 1H), 8.07 (d, J=6.5 Hz, 1H), 4.56-4.52 (m, 1H), 4.47-4.37 (m, 2H),4.09-4.01 (m, 1H), 2.86 (s, 3H), 1.27-1.25 (m, 1H), 1.12 (dd, J=6.5 Hz,3.0 Hz, 3H), 1.04 (dd, J=6.5 Hz, 2.0 Hz, 3H), 0.78-0.75 (m, 1H),0.65-0.60 (m, 1H), 0.59-0.50 (m, 2H). LC-MS m/z: 426.1 [M+H]⁺. HPLC:Purity (254 nm): >99%; t_(R)=8.91 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4,4-dimethyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and 4,4-dimethylimidazolidin-2-one afforded thetitle compound (32 mg, 26%) as a white solid. 1H NMR (500 MHz, MeOD-d₄)δ 8.43 (s, 1H), 8.16 (s, 1H), 4.42-4.39 (m, 1H), 3.97 (d, J=10.5 Hz,1H), 3.92 (d, J=10.5 Hz, 1H), 2.80 (s, 3H), 1.443 (s, 3H), 1.435 (s,3H), 1.29-1.25 (m, 1H), 0.79-0.75 (m, 1H), 0.67-0.63 (m, 1H), 0.59-0.54(m, 1H), 0.53-0.49 (m, 1H). LC-MS m/z: 411.1 [M+H]⁺. HPLC Purity (214nm): >99%; t_(R)=7.70 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a mixture of 2-amino-3-methylbutanoic acid (15 g, 128 mmol), andNaBH₄ (19.5 g, 512 mmol) in THF (200 mL) was added I₂ (32 g, 128 mmol,dissolved in 100 mL of THF) dropwise at 0° C. The reaction mixture wasstirred at 65° C. for 16 h, quenched with MeOH (100 mL) and concentratedin vacuo. The white residue was dissolved in 225 mL of 20% aqueous KOHand stirred for 3 h at RT, extracted with EA (100 mL×3), and the organicphases dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to afford 2-amino-3-methylbutan-1-ol (7 g, 50%) asan oil. LC-MS m/z: 118.1 [M+H]⁺. Purity (214 nm): 90%; t_(R)=0.34 min.

To a mixture of 2-amino-3-methylbutan-1-ol (7 g, 60 mmol), and Na₂CO₃(22 g, 180 mmol) in H₂O (100 mL) was added benzyl chloroformate (12 g,66 mmol). The mixture was stirred at RT for 16 h, and extracted with EA(50 mL×3) and dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo, and the residue was purified by silica gel columnchromatography (EA:PE=1:3) to afford benzyl1-hydroxy-3-methylbutan-2-ylcarbamate (9 g, 65%) as a white solid. LC-MSm/z: 238.1 [M+H]⁺. Purity (214 nm): 90%; t_(R)=1.62 min.

To a mixture of benzyl 1-hydroxy-3-methylbutan-2-ylcarbamate (1 g, 4.2mmol), and Et₃N (850 mg, 8.4 mmol) in toluene (15 mL) was added MsCl(480 mg, 4.2 mmol). The mixture was stirred at RT for 15 minutes,followed by the addition of a solution of NaN₃ (2.7 g, 42 mmol) in 20 mLof water, and Bu₄NBr (680 mg, 2.1 mmol). The resulting mixture wasstirred at 90° C. for 16 h, extracted with DCM (30 mL×3), dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo toafford benzyl 1-azido-3-methylbutan-2-ylcarbamate (1.1 g, 90%) as awhite oil, which was used directly in the next step. LC-MS m/z: 263.1[M+H]⁺. Purity (214 nm): 90%; t_(R)=1.86 min.

A mixture of benzyl 1-azido-3-methylbutan-2-ylcarbamate (1.1 g, 4.2mmol), triphenylphosphine (1.6 g, 6.3 mmol), and H₂O (1 g, 42 mmol) inTHF (20 mL) was stirred at RT for 16 h, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography (EA:PE=1:3) toafford benzyl 1-amino-3-methylbutan-2-ylcarbamate (900 mg, 90%) as awhite solid. LC-MS m/z: 237.1 [M+H]⁺. Purity (214 nm): 90%; t_(R)=1.50min.

A mixture of benzyl 1-amino-3-methylbutan-2-ylcarbamate (100 mg, 0.42mol), 10% Pd/C (100 mg, 0.47 mmol), and 4M HCl/dioxane (2 mL) in MeOH(10 mL) was stirred for 3 h at 30° C. under H₂, and filtered. Thefiltrate was concentrated in vacuo to afford 3-methylbutane-1,2-diamine(40 mg, crude) as a colorless oil.

A mixture of 3-methylbutane-1,2-diamine (40 mg, crude), CDI (129 mg,0.78 mmol), Et₃N (88 mg, 0.87 mmol) in DCM (10 mL) was stirred for 18 hat 30° C., and concentrated in vacuo. The residue was dissolved in H₂O(5 mL), which was adjusted to pH=6-7, and extracted with DCM (20 mL×3).The organic phases were dried over anhydrous Na₂SO₄ and filtered. Thefiltrate was concentrated in vacuo to afford4-iso-propylimidazolidin-2-one (23 mg, crude) as a light yellow solid.

Following general procedure H,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(59.7 mg, 0.18 mmol) and 4-iso-propylimidazolidin-2-one afforded thetitle compound (8 mg, 4% over three steps) as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.43 (s, 1H), 8.24 (dd, J=23.5 Hz, 8.0 Hz, 1H), 8.18(d, J=5.0 Hz, 1H), 8.08 (s, 1H), 4.48-4.42 (m, 1H), 4.18 (dd, J=10.5 Hz,9.0 Hz, 1H), 4.09 (t, J=10.0 Hz, 1H), 3.75 (dd, J=9.5 Hz, 6.5 Hz, 1H),3.68 (dd, J=11.0 Hz, 6.5 Hz, 1H), 3.57-3.32 (m, 1H), 2.73 (s, 3H),1.73-1.67 (m, 1H), 1.21-1.16 (m, 1H), 0.91 (dd, J=7.0 Hz, 1.5 Hz, 3H),0.87 (dd, J=6.5 Hz, 4.0 Hz, 3H), 0.67-0.62 (m, 1H), 0.56-0.49 (m, 2H),0.40-0.35 (m, 1H). LC-MS m/z: 425.2 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.14 min.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-(2-methylbenzo[d]oxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.29 mmol) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazoleafforded the title compound (3.1 mg, 3%) as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.57 (d, J=1.5 Hz, 1H), 8.55 (s, 1H), 8.30 (dd, J=8.5Hz, 1.5 Hz, 1H), 8.22 (d, J=7.5 Hz, 1H), 8.00 (s, 1H), 7.91 (d, J=8.5Hz, 1H), 3.67-3.63 (m, 1H), 2.86 (s, 3H), 2.68 (s, 3H), 1.30 (d, J=6.5Hz, 3H), 1.13-1.09 (m, 1H), 0.57-0.50 (m, 2H), 0.42-0.39 (m, 1H),0.37-0.34 (m, 1H). LC-MS m/z: 376.1 [M+H]⁺. HPLC Purity (214 nm): 97.4%;t_(R)=8.09 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4,4-dimethyl-3,4-dihydro-2H-pyran-6-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution of 4,4-dimethyltetrahydro-2H-pyran-2-one (4.3 g,33.5 mmol) in DCM (150 ml) at −78° C., was added a solution of DIBAL-H(36.9 ml, 36.9 mmol) in toluene over 1 h. The resulting solution wasstirred for an additional 30 min, quenched with MeOH (25 ml) and allowedto warm slowly to RT overnight. The resulting suspension was dilutedwith 30% aqueous solution of sodium potassium tartrate (200 ml) andstirred for 30 min, the organic layer was separated and washed with 30%aqueous sodium potassium tartrate (100 mL×2). The combined aqueouslayers were then extracted with DCM (100 mL×3). The combined organiclayers were dried over anhydrous Na₂SO₄ and filtered. The filtrate wasconcentrated in vacuo to give crude 4,4-dimethyltetrahydro-2H-pyran-2-ol(4.3 g, 100%) as a clear liquid. ¹H NMR (400 MHz, DMSO-d₆) δ 6.20 (d,J=6.0 Hz, 1H), 4.72-4.68 (m, 1H), 3.75-3.70 (m, 1H), 3.51 (td, J=10.8Hz, 2.8 Hz, 1H), 1.39-1.36 (m, 1H), 1.31-1.24 (m, 1H), 1.18-1.09 (m,2H), 0.94 (s, 6H).

4,4-Dimethyltetrahydro-2H-pyran-2-ol (0.62 g, 4.76 mmol) was addeddropwise to a solution of p-TsOH (80 mg) in quinoline (5 mL) preheatedto 190° C. attached to a short-path distillation apparatus equipped witha dry ice/acetone filled cold trap. After the addition was complete thetemperature was raised to 220° C., and the distillation was carried outto afford 4,4-dimethyl-3,4-dihydro-2H-pyran (220 mg, 40%) as a clearliquid. ¹H NMR (400 MHz, DMSO-d₆) δ 6.25 (d, J=6.4 Hz, 1H), 4.50 (d,J=6.4 Hz, 1H), 3.89 (t, J=5.2 Hz, 2H), 1.58 (t, J=5.2 Hz, 2H), 0.99 (s,6H).

To a solution of 4,4-dimethyl-3,4-dihydro-2H-pyran (1.0 g, 8.93 mmol) inhexane (40 mL) was added4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (2.27 g,8.93 mmol), [Ir(OMe)(cod)]₂ (298 mg, 0.45 mmol) and4,4′-di-tert-butyl-2,2′bipyridyl (238 mg, 0.89 mmol). The mixture wasstirred for 20 h at reflux under N₂, cooled to RT and concentrated togive a residue which was purified by silica gel column chromatography(PE:EA=5:1) to afford2-(4,4-dimethyl-3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(900 mg, 42%) as a colorless oil. LC-MS m/z: 239.2 [M+H]⁺. Purity (214nm): 26%; t_(R)=1.67 min.

Following general procedure D,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(348 mg, 1.05 mmol) and2-(4,4-dimethyl-3,4-dihydro-2H-pyran-6-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneafforded the title compound (170 mg, 39%) as a white solid. ¹H NMR (400MHz, CDCl₃) δ 8.63 (s, 1H), 8.59 (d, J=9.6 Hz, 1H), 7.21 (s, 1H), 6.12(s, 1H), 4.63-4.57 (m, 1H), 4.24 (dd, J=6.0 Hz, 4.0 Hz, 2H), 2.84 (s,3H), 1.79 (t, J=4.8 Hz, 2H), 1.26-1.19 (m, 1H), 1.15 (s, 6H), 0.70-0.65(m, 1H), 0.61-0.49 (m, 3H). LC-MS m/z: 409.0 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=10.15 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4,4-dimethyltetrahydro-2H-pyran-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution ofN-(1-cyclopropyl-2,2,2-trifluoroethyl)-5-(4,4-dimethyl-3,4-dihydro-2H-pyran-6-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.20 mmol) in THF (20 mL) at RT was added 5% Pd/C (10 mg) undera H₂ atmosphere and the mixture was stirred at RT for 2 h. The crudereaction mixture was eluted through a short plug of celite (EA followedby DCM) and the organic layer was concentrated in vacuo to provide aresidue which was purified by preparative HPLC to afford the titlecompound (47 mg, 60%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.62(s, 1H), 8.47 (d, J=10.0 Hz, 1H), 7.34 (s, 1H), 4.72 (dd, J=12.0 Hz, 2.5Hz, 1H), 4.59-4.53 (m, 1H), 3.98-3.95 (m, 1H), 3.83-3.80 (m, 1H), 2.81(s, 3H), 1.79-1.76 (m, 1H), 1.50-1.34 (m, 3H), 1.21-1.20 (m, 1H), 1.13(s, 3H), 0.97 (s, 3H), 0.65-0.64 (m, 1H), 0.58-0.57 (m, 1H), 0.49-0.48(m, 1H), 0.43-0.41 (m, 1H). LC-MS m/z: 411.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=10.12 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(pyridazin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.3 mmol) and 3-(tributylstannyl)pyridazine afforded the titlecompound (10 mg, 9%) as a light yellow solid. 1H NMR (500 MHz, DMSO-d₆):δ 9.99 (dd, J=2.5 Hz, 1.5 Hz, 1H), 9.57 (dd, J=5.5 Hz, 1.5 Hz, 1H), 8.78(s, 1H), 8.46 (d, J=9.5 Hz, 1H), 8.39 (dd, J=5.5 Hz, 3.0 Hz, 1H), 8.16(s, 1H), 4.45-4.40 (m, 1H), 2.92 (s, 3H), 1.39-1.35 (m, 1H), 0.73-0.70(m, 1H), 0.63-0.59 (m, 2H), 0.41-0.39 (m, 1H). LC-MS m/z: 377.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=6.92 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(pyridazin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 4-(tributylstannyl)pyridazine afforded the titlecompound (33 mg, 37%) as a grey solid. ¹H NMR (500 MHz, DMSO-d₆): δ 9.99(s, 1H), 9.57 (d, J=5.5 Hz, 1H), 8.78 (s, 1H), 8.46 (d, J=9.5 Hz, 1H),8.39 (dd, J=5.5 Hz, 3.0 Hz, 1H), 8.17 (s, 1H), 4.45-4.40 (m, 1H), 2.91(s, 3H), 1.39-1.34 (m, 1H), 0.74-0.71 (m, 1H), 0.64-0.57 (m, 2H),0.40-0.37 (m, 1H). LC-MS m/z: 377.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=6.92 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (65 mg, 0.21 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (12.4 mg, 14%) as a whitesolid. ¹H NMR (500 MHz, CDCl₃): δ 8.51 (s, 1H), 8.17 (d, J=9.5 Hz, 1H),8.15 (s, 1H), 4.52-4.47 (m, 1H), 4.33-4.27 (m, 1H), 4.12-4.06 (m, 2H),3.57 (t, J=7.0 Hz, 2H), 2.78 (s, 3H), 1.25 (d, J=7.0 Hz, 6H), 1.14-1.10(m, 1H), 0.71-0.67 (m, 1H), 0.57-0.50 (m, 3H). LC-MS m/z: 425.1 [M+H]⁺.HPLC Purity (214 nm): >99%; t_(R)=8.60 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(3-iso-propyl-2-oxoimidazolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (65 mg, 0.21 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (5.6 mg, 6%) as a white solid.¹H NMR (500 MHz, CDCl₃): δ 8.50 (s, 1H), 8.17 (d, J=9.5 Hz, 1H), 8.15(s, 1H), 4.52-4.47 (m, 1H), 4.33-4.27 (m, 1H), 4.12-4.06 (m, 2H), 3.57(t, J=7.0 Hz, 2H), 2.78 (s, 3H), 1.25 (d, J=7.0 Hz, 6H), 1.14-1.10 (m,1H), 0.71-0.67 (m, 1H), 0.57-0.50 (m, 3H). LC-MS m/z: 425.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.60 min.

N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3,3-dimethyl-2-oxopyrrolidin-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H,5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and 3,3-dimethylpyrrolidin-2-one afforded the titlecompound (20 mg, 16%) as a yellow solid. 1H NMR (500 MHz, DMSO-d₆): δ8.53 (s, 1H), 8.19 (d, J=9.0 Hz, 1H), 8.18 (s, 1H), 4.38-4.31 (m, 1H),4.11-4.01 (m, 1H), 3.41-3.31 (m, 1H), 2.78 (s, 3H), 2.04 (t, J=7.0 Hz,2H), 1.30-1.24 (m, 1H), 1.24 (s, 6H), 0.71-0.65 (m, 1H), 0.68-0.55 (m,2H), 0.42-0.32 (m, 1H). LC-MS m/z: 410.2 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.94 min.

(R)-7-Methyl-5-(2-oxo-3-phenylimidazolidin-1-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.326 mmol) and 1-phenylimidazolidin-2-one afforded the titlecompound (18.3 mg, 13%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.49 (s, 1H), 8.17 (s, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.69 (d, J=7.5 Hz,2H), 7.44 (t, J=8.0 Hz, 2H), 7.17 (t, J=7.5 Hz, 1H), 4.94-4.92 (m, 1H),4.26-4.07 (m, 4H), 2.79 (s, 3H), 1.44 (d, J=6.5 Hz, 3H). LC-MS m/z:433.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=8.75 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(2-oxo-3-phenylimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(94 mg, 0.28 mmol) and 1-phenylimidazolidin-2-one afforded the titlecompound (30 mg, 23%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.54(s, 1H), 8.20 (d, J=0.8 Hz, 1H), 8.15 (d, J=6.0 Hz, 1H), 7.62 (dd, J=8.8Hz, 1.2 Hz, 2H), 7.44 (td, J=8.4 Hz, 2.0 Hz, 2H), 7.21 (t, J=7.6 Hz,1H), 4.51-4.49 (m, 1H), 4.28-4.23 (m, 2H), 4.13-4.08 (m, 2H), 2.82 (s,3H), 1.15-1.13 (m, 1H), 0.73-0.70 (m, 1H), 0.58-0.52 (m, 3H). LC-MS m/z:459.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=9.22 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(4,5-dimethyloxazol-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution of 4,5-dimethyloxazole (150 mg, 1.55 mmol) inanhydrous THF (10 mL) was added n-BuLi (0.62 mL, 1.55 mmol) dropwise at−78° C. The mixture was stirred for 30 minutes and then 1M ZnCl₂ (3.87mL, 3.87 mol) was added at −78° C., stirred an additional 30 minutes andwarmed to RT.(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(90 mg, 0.27 mmol) was added followed by Pd(PPh₃)₂Cl₂ (18.9 mg, 0.027)and the mixture was stirred at 60° C. for 3 h under N₂ and concentratedin vacuo. The residue was purified by silica gel column chromatography(EA/PE=80%) to afford the title compound (18 mg, 17%) as a white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.51 (d, J=9.6 Hz, 1H), 7.82(s, 1H), 4.64-4.60 (m, 1H), 2.86 (s, 3H), 2.43 (s, 3H), 2.19 (s, 3H),1.27-1.23 (m, 1H), 0.68-0.58 (m, 3H), 0.54-0.48 (m, 1H). LC-MS m/z:394.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=11.36 min.

(R)—N-(1-Cycloprop-2,2,2-trifluoroethyl)-5-(2-iso-propyl-5-methyloxazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution of ethyl5-formyl-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (0.3 g, 1.29mmol) in THF (3 mL) was added EtMgBr₂ (1.42 mL, 1.42 mmol) at −78° C.and the solution was stirred at −78° C. for 1.5 h and then quenched withsaturated NH₄Cl (10 mL). The mixture was extracted with EA (20 mL) theorganic layer was washed with H₂O (10 mL) and brine (10 mL), dried overanhydrous Na₂SO₄ and concentrated in vacuo and purified by silica gelchromatography (PE/EA=2:3) to afford ethyl5-(1-hydroxypropyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (70mg, 20%) as a yellow oil. LC-MS m/z: 264.2 [M+H]⁺. Purity (214 nm): 93%;t_(R)=1.09 min.

To a stirred solution of ethyl5-(1-hydroxypropyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (70mg, 0.27 mmol) in DCM (3 mL) was added Dess-Martin reagent (223 mg, 0.54mmol) at 0° C. under N₂ and the solution was stirred at RT overnight.The reaction was quenched with saturated NaHCO₃ (10 mL), extracted withDCM (20 mL), washed with H₂O (10 mL) and brine (10 mL), dried overanhydrous Na₂SO₄ and concentrated in vacuo and purified by silica gelchromatography (PE/EA=2:1) to give ethyl7-methyl-5-propionylpyrazolo[1,5-a]pyrimidine-3-carboxylate (50 mg, 72%)as a yellow solid. LC-MS m/z: 262.1 [M+H]⁺. Purity (254 nm): 96%;t_(R)=1.88 min.

To a solution of ethyl7-methyl-5-propionylpyrazolo[1,5-a]pyrimidine-3-carboxylate (70 mg, 0.27mmol) in MeOH (5 mL) was added HONH₂.HCl (186 mg, 2.68 mmol) and TEA(183 mg, 1.34 mmol) and the mixture was stirred at RT for 3 h. Then itwas poured into H₂O (20 mL) and extracted with EA (15 mL×2). Thecombined extracts were washed with brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give ethyl5-(1-(hydroxyimino)propyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(70 mg, 95%) as a white solid. LC-MS (m/z): 277.2 [M+H]⁺, Purity (214nm): 95%, t_(R)=1.24 min.

To a solution of ethyl5-(1-(hydroxyimino)propyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 0.36 mmol) and DMAP (3.0 mg, 0.023 mmol) in 1,2-dichlorobenzene(1 mL) at 0° C. was added dropwise iso-butyryl chloride (385 mg, 3.6mmol). The reaction mixture was heated at 180° C. for 1 h undermicrowave conditions, cooled, concentrated and then purified by silicagel chromatography (EA) to give ethyl5-(2-iso-propyl-5-methyloxazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(70 mg, 59%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (s,1H), 7.64 (s, 1H), 4.30 (q, J=7.0 Hz, 2H), 2.89 (s, 3H), 2.81 (s, 3H),2.48 (s, 3H), 1.34 (t, J=7.0 Hz, 3H). LC-MS (m/z): 300.1 [M+H]⁺,t_(R)=1.32 min.

Following general procedure B*, ethyl5-(2-iso-propyl-5-methyloxazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(70 mg, 0.21 mmol) afforded5-(2-iso-propyl-5-methyloxazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (69 mg, 100%). LC-MS (m/z): 301.1 [M+H]⁺, Purity (214 nm): 79%,t_(R)=1.17 min.

Following general procedure A,5-(2-iso-propyl-5-methyloxazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (70 mg, 0.21 mmol) and(R)-1-cyclopropyl-2,2,2-trifluoroethan-1-amine afforded the titlecompound (29 mg, 33%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.64(s, 1H), 8.18 (d, J=9.5 Hz, 1H), 7.67 (s, 1H), 4.34-4.28 (m, 1H),3.18-3.12 (m, 1H), 2.85 (s, 3H), 2.79 (s, 3H), 1.35 (s, 3H), 1.33 (s,3H), 1.23-1.15 (m, 1H), 0.75-0.55 (m, 3H), 0.35-0.3 (m, 1H). LC-MS m/z:422.2 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=10.16 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(2,5-dimethyloxazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of ethyl5-(1-(hydroxyimino)propyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(70 mg, 0.25 mmol) and DMAP (2.0 mg, 0.016 mmol) in 1,2-dichlorobenzene(0.5 mL) at 0° C. was added dropwise acetyl chloride (40 mg, 0.51 mmol).The reaction mixture was heated at 180° C. for 45 min under microwaveconditions, cooled, concentrated and then purified by silica gelchromatography (PE/EA=1:5) to give ethyl5-(2,5-dimethyloxazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(30 mg, 40%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.61 (s, 1H),7.64 (s, 1H), 4.30 (q, J=7.0 Hz, 2H), 2.89 (s, 3H), 2.81 (s, 3H), 2.48(s, 3H), 1.34 (t, J=7.0 Hz, 3H). LC-MS (m/z): 300.1 [M+H]⁺, t_(R)=1.32min.

Following general procedure B*, ethyl5-(2,5-dimethyloxazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(30 mg, 0.1 mmol) afforded crude5-(2,5-dimethyloxazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 100%) as a brown solid. LC-MS (m/z): 273.1 [M+H]⁺, Purity(214 nm): 74%, t_(R)=1.04 min.

Following general procedure A,5-(2,5-dimethyloxazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.1 mmol) and(R)-1-cyclopropyl-2,2,2-trifluoroethan-1-amine afforded the titlecompound (6.4 mg, 16%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.64 (s, 1H), 8.18 (d, J=9.5 Hz, 1H), 7.69 (s, 1H), 4.33-4.26 (m, 1H),2.84 (s, 3H), 2.78 (s, 3H), 2.49 (s, 3H), 1.20-1.16 (m, 1H), 0.77-0.62(m, 2H), 0.60-0.55 (m, 1H), 0.35-0.25 (m, 1H). LC-MS m/z: 394.0 [M+H]⁺.HPLC Purity (214 nm): >99%; t_(R)=8.88 min.

(R)-5-(5-Fluorofuran-2-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.16 mmol) and tributyl(5-fluorofuran-2-yl)stannane afforded thetitle compound (37 mg, 64%) as a white solid. ¹H NMR (400 MHz, MeOD-d₄)δ 8.55 (s, 1H), 7.42 (s, 1H), 7.39 (d, J=4.5 Hz, 1H), 5.98 (dd, J=8.5Hz, 4.5 Hz, 1H), 4.95-4.93 (m, 1H), 2.86 (s, 3H), 1.52 (d, J=8.5 Hz,3H). LC-MS m/z: 357.1 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=8.62min.

(R)-5-(2-Fluorofuran-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of 3-bromofuran-2-carboxylic acid (300 mg, 1.57 mmol) andNaHCO₃ (316 mg, 3.76 mmol) was stirred in 3.5 mL of pentane/water (2/5)at RT for 5 minutes, followed by the addition of1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis-tetrafluoroborate(668 mg, 1.88 mmol). The mixture was stirred for 1 hour at RT, andseparated to afford the pentane solution of 3-bromo-2-fluorofuran, whichwas dried (MgSO₄), diluted with 3 mL of anhydrous Et₂O, and cooled to−78° C. under N₂. To this was added n-BuLi (1.6M, 0.25 mL, 0.39 mmol)and the mixture was stirred at −78° C. for 10 minutes, followed by theaddition of n-Bu₃SnCl (127 mg, 0.39 mmol). The mixture was then allowedto stir at RT for another 20 minutes, quenched with saturated NH₄Cl (50mL), and separated. The organic phase was dried over anhydrous MgSO₄,filtered and concentrated in vacuo to affordtributyl(2-fluorofuran-3-yl)stannane (155 mg) as a brown oil which wasused directly in the next step.

Following general procedure F,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and tributyl(2-fluorofuran-3-yl)stannane afforded thetitle compound (6.8 mg, 13%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 8.63 (s, 1H), 8.41 (d, J=9.0 Hz, 1H), 7.57 (d, J=2.5 Hz, 1H),7.56 (s, 1H), 7.21 (t, J=2.5 Hz, 1H), 4.98-4.92 (m, 1H), 2.82 (s, 3H),1.42 (d, J=7.5 Hz, 3H). LC-MS m/z: 357.0 [M+H]⁺. HPLC: Purity (214 nm):97%; t_(R)=8.52 min.

(R)-7-Methyl-5-(4-methylfuran-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(700 mg, 2.29 mmol), Pd(PPh₃)₂Cl₂(160 mg, 0.23 mmol) and Sn₂Bu₆ (2.6 g,4.58 mmol) in dioxane (40 mL) was stirred at 80° C. for 16 h under N₂.The reaction mixture was filtered and concentrated in vacuo and purifiedby silica gel chromatography (PE:EA=4:1) to afford(R)-7-methyl-5-(tributylstannyl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(400 mg, 32%) as a white solid. LC-MS m/z: 562.0 [M+H]⁺, Purity (214nm): 95%; t_(R)=2.22 min.

Following general procedure F,(R)-7-methyl-5-(tributylstannyl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(400 mg, 0.71 mmol) and 3,4-dibromofuran afforded(R)-5-(4-bromofuran-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 34%) as a white solid. LC-MS m/z: 417.0 [M+H]⁺, Purity (214nm): 95%; t_(R)=1.47 min.

A mixture of(R)-5-(4-bromofuran-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.24 mmol), (P(o-Tol)₃)₂PdCl₂ (17 mg, 0.024 mmol), SnMe₄ (86mg, 0.48 mmol) in dioxane (3 mL)/DMF (1 mL) was stirred at 120° C. underN₂ and microwave for 30 min. The reaction mixture was filtered andconcentrated in vacuo to give a residue which was purified bypreparative HPLC to afford the title compound (5 mg, 6%) as a whitesolid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.65 (d, J=1.5 Hz, 1H), 8.59 (s, 1H),8.04 (d, J=9.0 Hz, 1H), 7.72 (s, 1H), 7.63 (s, 1H), 4.07-4.00 (m, 1H),2.78 (s, 3H), 2.40 (s, 3H), 1.40 (d, J=7.5 Hz, 3H). LC-MS m/z: 353.0[M+H]⁺, HPLC: Purity (214 nm): >99%; t_(R)=8.74 min.

(R)-5-(Furan-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and 3-bromofuran afforded the title compound (5 mg,5%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.59 (s,1H), 8.41 (d, J=9.5 Hz, 1H), 7.95 (d, J=1.5 Hz, 1H), 7.67 (s, 1H), 7.06(d, J=1.0 Hz, 1H), 4.99-4.9 (m, 1H), 2.80 (s, 3H), 1.46 (d, J=6.5 Hz,3H). LC-MS m/z: 339.0 [M+H]⁺, HPLC: Purity (214 nm): >99%; t_(R)=8.28min.

(R)-7-Methyl-5-(5-methylfuran-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(120 mg, 0.40 mmol) and 4-bromo-2-methylfuran afforded the titlecompound (5.7 mg, 4%) as a grey solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.58(s, 1H), 8.51 (s, 1H), 8.41 (d, J=9.5 Hz, 1H), 7.61 (s, 1H), 6.65 (s,1H), 4.96-4.92 (m, 1H), 2.78 (s, 3H), 2.38 (s, 3H), 1.46 (d, J=7.0 Hz,3H). LC-MS m/z: 353.1 [M+H]⁺. HPLC: Purity (214 nm): 97%; t_(R)=8.77min.

(S)-7-Methyl-5-(5-methylfuran-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(110 mg, 0.36 mmol) and 4-bromo-2-methylfuran afforded the titlecompound (10.4 mg, 8%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.58 (s, 1H), 8.51 (s, 1H), 8.41 (d, J=10.0 Hz, 1H), 7.61 (s, 1H), 6.65(s, 1H), 4.99-4.90 (m, 1H), 2.78 (s, 3H), 2.38 (s, 3H), 1.46 (d, J=7.0Hz, 3H). LC-MS m/z: 353.2 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.81 min.

(R)-7-Methyl-5-(2-methylfuran-3-yl)-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(40 mg, 0.130 mmol) and4,4,5,5-tetramethyl-2-(2-methylfuran-3-yl)-1,3,2-dioxaborolane affordedthe title compound (10 mg, 17%) as a white solid. ¹H NMR (400 MHz,MeOD-d₄) δ 8.61 (s, 1H), 8.11 (d, J=9.6 Hz, 1H), 7.75 (d, J=2.0 Hz, 1H),7.58 (s, 1H), 7.14 (d, J=1.6 Hz, 1H), 5.02-4.97 (m, 1H), 2.81 (s, 3H),2.75 (s 3H), 1.42 (d, J=6.8 Hz, 3H). LC-MS m/z: 353.1 [M+H]⁺. HPLC:Purity (214 nm): >99%; t_(R)=8.61 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(5-methylisoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of ethyl5-formyl-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (300 mg, 1.28mmol) and 1-(tritylphosphanylidene)propan-2-one (389 mg, 1.28 mmol) inTHF (20 mL) was heated at reflux for 0.5 h. The reaction wasconcentrated and then triturated with Et₂O (20 ml) to afford ethyl(E)-7-methyl-5-(3-oxobut-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(295 mg, 85%) as a white solid. LC-MS m/z: 274.1[M+H]⁺. Purity (214 nm):96%; t_(R)=1.13 min.

To a solution of N-hydroxy-4-methylbenzenesulfonamide (500 mg, 2.59mmol) in 1.8 mL of MeOH/H₂O (6/1) was added in portions K₂CO₃ (408 mg,2.96 mmol) followed by the addition of ethyl(E)-7-methyl-5-(3-oxobut-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 0.37 mmol) in MeOH (3 mL) and the reaction mixture was stirredfor 3 h at 40° C. Additional K₂CO₃ (200 mg) was added and the mixturewas stirred for 8 h at 60° C. The reaction mixture was diluted with EA(80 mL), washed with H₂O (15 mL) and brine (15 mL), dried over Na₂SO₄and filtered. The filtrate was concentrated in vacuo, and the residuewas purified by silica gel chromatography (PE:EA=1:1) to afford ethyl7-methyl-5-(5-methylisoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(86 mg, 86%) as a yellow solid. LC-MS m/z: 273.1[M+H]⁺. Purity (214 nm):65%; t_(R)=1.19 min.

Following general procedure B*, ethyl7-methyl-5-(5-methylisoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(86 mg, 0.32 mmol) afforded7-methyl-5-(5-methylisoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (72 mg, 90%) as a yellow solid. LC-MS m/z: 259.1 [M+H]⁺. LCMS:Purity (214 nm): 95%; t_(R)=0.75 min.

Following general procedure A,7-methyl-5-(5-methylisoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (65 mg, 0.25 mmol) and(R)-1-cyclopropyl-2,2,2-trifluoroethan-1-amine afforded the titlecompound (39 mg, 41%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.72(s, 1H), 8.39 (d, J=10.0 Hz, 1H), 7.83 (s, 1H), 6.78 (s, 1H), 4.29-4.37(m, 1H), 2.88 (s, 3H), 2.57 (s, 3H), 1.38-1.35 (m, 1H), 0.70-0.68 (m,1H), 0.61-0.58 (m, 2H), 0.40-0.37 (m, 1H). LC-MS m/z: 380.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=8.93 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(4-methylisoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of ethyl5-formyl-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (320 mg, 1.37mmol) and 2-(tritylphosphanylidene)propanal (436 mg, 1.37 mmol) in THF(20 mL) was heated at reflux for 0.5 h. The reaction was concentratedand then triturated with Et₂O (20 mL) to afford ethyl(E)-7-methyl-5-(2-methyl-3-oxoprop-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(310 mg, 83%) as a yellow solid. LC-MS m/z: 274.1[M+H]⁺. Purity (214nm): 96%; t_(R)=1.77 min.

To a solution of N-hydroxy-4-methylbenzenesulfonamide (277 mg, 1.48mmol) in 1.8 mL of MeOH/H₂O (6/1) was added in portions K₂CO₃ (255 mg,1.48 mmol) followed by the addition of ethyl(E)-7-methyl-5-(2-methyl-3-oxoprop-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 0.37 mmol) in MeOH (5 mL) and the reaction mixture was stirredfor 18 h at RT. Additional K₂CO₃ (100 mg) was added and the mixture wasstirred for 4 h at 60° C. The reaction mixture was diluted with EA (80mL), washed with H₂O (15 mL) and brine (15 mL) and dried over Na₂SO₄ andfiltered. The filtrate was concentrated in vacuo, and the residue waspurified by silica gel chromatography (PE:EA=1:1) to afford ethyl7-methyl-5-(4-methylisoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(62 mg, 61%) as a yellow solid. LC-MS m/z: 273.0[M+H]⁺. Purity (214 nm):83%; t_(R)=1.72 min.

Following general procedure B*, ethyl7-methyl-5-(4-methylisoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(62 mg, 0.23 mmol) afforded7-methyl-5-(4-methylisoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (25 mg, 42%) as a yellow solid. LC-MS m/z: 259.0[M+H]⁺. LCMS:Purity (214 nm): 80%; t_(R)=1.17 min.

Following general procedure A,7-methyl-5-(4-methylisoxazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (25 mg, 0.10 mmol) and(R)-1-cyclopropyl-2,2,2-trifluoroethan-1-amine afforded the titlecompound (14.0 mg, 27%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ9.01 (s, 1H), 8.74 (s, 1H), 8.15 (d, J=9.5 Hz, 1H), 7.84 (s, 1H),4.31-4.28 (m, 1H), 2.88 (s, 3H), 2.41 (s, 3H), 1.18-1.15 (m, 1H),0.73-0.66 (m, 2H), 0.58-0.55 (m, 1H), 0.33-0.31 (m, 1H). LC-MS m/z:380.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.83 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(3-methylisoxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A suspension of ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (480 mg, 2mmol), ethynyltrimethylsilane (392 mg, 2 mmol), Pd(PPh₃)Cl₂ (140 mg, 0.2mmol), CuI (38 mg, 0.2 mmol), and Et₃N (404 mg, 4 mmol) in THF (5 mL)was stirred at RT for 0.5 hour under N₂ atmosphere, and then at 50° C.for 2 h. The reaction mixture was cooled to RT, quenched with saturatedNH₄Cl (20 mL), and extracted with EA (30 mL×3). The combined organiclayers were washed with brine (30 mL), dried (Na₂SO₄) and filtered. Thefiltrate was concentrated in vacuo, and the residue was purified bysilica gel column chromatography (PE/EA: 2/1) to afford ethyl7-methyl-5-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(540 mg, 89%) as a pale yellow solid. LC-MS m/z: 302.1 [M+H]⁺. LCMS:Purity (214 nm): 95.6%; t_(R)=1.56 min.

To a solution of ethyl7-methyl-5-((trimethylsilyl)ethynyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(150 mg, 0.5 mmol) in MeOH (10 mL) was added KF (58 mg, 1 mmol). Thereaction mixture was stirred at RT for 10 minutes, and concentrated invacuo after the addition of silica gel. The residue was purified bysilica gel column chromatography (PE/EA: 1/2) to afford ethyl5-ethynyl-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (89 mg, 79%)as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s, 1H), 7.40 (s,1H), 4.84 (s, 1H), 4.31 (q, J=7.0 Hz, 2H), 2.76 (s, 3H), 1.32 (t, J=7.0Hz, 3H). LC-MS m/z: 230.1 [M+H]⁺. LCMS: Purity (254 nm): 99%; t_(R)=1.15min.

To a solution of ethyl5-ethynyl-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (46 mg, 0.2mmol), and acetaldehyde oxime (89 mg, 1.5 mmol) in MeOH/H₂O (5/1, 2 mL)was added bis-[(trifluoroacetoxy) iodo]benzene (130 mg, 0.3 mmol). Thereaction mixture was stirred at RT for 12 h, concentrated in vacuo andpurified by silica gel column chromatography (PE/EA: 2/1) to affordethyl7-methyl-5-(3-methylisoxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(50 mg, 84%) as a pale yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 8.63 (s,1H), 7.49 (s, 1H), 7.10 (s, 1H), 4.44 (q, J=7.2 Hz, 2H), 2.92 (s, 3H),2.43 (s, 3H), 1.46 (t, J=6.8 Hz, 3H). LC-MS m/z: 287.1 [M+Na]⁺. LCMS:Purity (214 nm): 79%; t_(R)=1.68 min.

Following general procedure B*, ethyl7-methyl-5-(3-methylisoxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(40 mg, 0.17 mmol) afforded7-methyl-5-(3-methylisoxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (40 mg, 80%) as a yellow solid. LC-MS m/z: 258.1 [M+H]⁺. LCMS:Purity (254 nm): 75%; t_(R)=0.99 min.

Following general procedure A,7-methyl-5-(3-methylisoxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylicacid (40 mg, 0.16 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (10 mg, 17%) as a pale yellowsolid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.38 (d, J=9.5 Hz, 1H),8.84 (s, 1H), 7.25 (s, 1H), 7.14 (d, J=1.5 Hz, 1H), 4.47-4.44 (m, 1H),2.88 (s, 3H), 2.40 (s, 3H), 1.36-1.32 (m, 1H), 0.70-0.67 (m, 1H),0.62-0.56 (m, 2H), 0.45-0.40 (m, 1H). LC-MS m/z: 380.1 [M+H]⁺. HPLC:Purity (214 nm): 97.9%; t_(R)=8.49 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(4-methylisoxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of(E)-7-methyl-5-(2-methyl-3-oxoprop-1-en-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(782 mg, 2.86 mmol), HONH₂ hydrochloride (296 mg, 4.29 mmol) and KOAc(420 mg, 4.29 mmol) in MeOH (10 mL) was stirred at RT overnight. Themixture was filtered to afford ethyl5-((1E,3Z)-3-(hydroxyimino)-2-methylprop-1-en-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(608 mg, 73%) as a yellow solid which was used directly in the nextstep. LC-MS m/z: 289.1[M+H]⁺. Purity (214 nm): 84%; t_(R)=1.15 min.

A mixture of ethyl5-((1E,3Z)-3-(hydroxyimino)-2-methylprop-1-en-1-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(500 mg, 1.74 mmol) and MnO₂ (1.5 g, 17.4 mmol) in CHCl₃ (30 mL) wasstirred at 65° C. overnight. Then the mixture was filtered and thefiltrate was concentrated in vacuo. The resulting residue was purifiedby silica gel chromatography (PE:EA=1:1) to afford ethyl7-methyl-5-(4-methylisoxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(120 mg, 24%) as a yellow solid. LC-MS m/z: 287.1[M+H]⁺. Purity (214nm): 80%; t_(R)=1.28 min.

To a stirred solution of (R)-1-cyclopropyl-2,2,2-trifluoroethan-1-aminehydrochloride (293 mg, 1.67 mmol) in toluene (2 mL) was added AlMe₃(0.98 mL, 1.96 mmol) at 0° C. and the solution was stirred at RT for 1h. Then a solution of ethyl7-methyl-5-(4-methylisoxazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(40 mg, 0.14 mmol) in THF (2 mL) was added and the reaction was stirredat 110° C. for 40 min. Saturated NH₄Cl (10 mL) solution was added andthe mixture was extracted with EA (20 mL), washed with H₂O (5 mL) andbrine (5 mL), concentrated in vacuo and purified by silica gelchromatography (PE:EA=2:3) and preparative HPLC to afford the titlecompound (12.7 mg, 23%) as a white solid. 1H NMR (500 MHz, DMSO-d₆) δ8.80 (s, 1H), 8.75 (s, 1H), 8.16 (d, J=9.5 Hz, 1H), 7.80 (s, 1H),4.35-4.30 (m, 1H), 2.90 (s, 3H), 2.51 (s, 3H), 1.19-1.17 (m, 1H),0.73-0.68 (m, 1H), 0.67-0.66 (m, 1H), 0.59-0.56 (m, 1H), 0.34-0.33 (m,1H). LC-MS m/z: 379.8 [M+H]⁺. HPLC: Purity (214 nm): 95%; t_(R)=8.65min.

(R)-5-(4,5-Dimethyloxazol-2-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a mixture of 4,5-dimethyloxazole (92 mg, 0.66 mmol) in THF (5 mL) wasadded n-BuLi (0.3 mL, 0.80 mmol) at −78° C., and the mixture was stirredat −78° C. for 30 minutes followed by the addition of ZnCl₂ (1.8 mL, 2.0mmol). The resulting mixture was stirred at −78° C. for 30 minutes,followed by the addition of(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.33 mmol), and Pd(PPh₃)₂Cl₂ (28 mg, 0.03 mmol), and stirred at65° C. for 16 h under N₂. The reaction mixture was filtered and filtratewas concentrated in vacuo, and the residue was purified by preparativeHPLC (MeCN/NH₄HCO₃) to afford the title compound (7 mg, 5%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.71 (s, 1H), 8.52 (d, J=8.8 Hz, 1H),7.81 (s, 1H), 4.97-4.91 (m, 1H), 2.86 (s, 3H), 2.41 (s, 3H), 2.19 (s,3H), 1.43 (d, J=7.2 Hz, 3H). LC-MS m/z: 368.1 [M+H]⁺. HPLC: Purity (214nm): 99%; t_(R)=8.36 min.

(S)—N-(1-Cyclopropylethyl)-7-methyl-5-(3-methylisothiazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(130 mg, 0.47 mmol) and 5-bromo-3-methylisothiazole afforded the titlecompound (31 mg, 19%) as a light yellow solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.61 (s, 1H), 8.06 (s, 1H), 7.87 (d, J=9.5 Hz, 1H), 7.86 (s, 1H),3.67-3.60 (m, 1H), 2.85 (s, 3H), 2.54 (s, 3H), 1.30 (d, J=7.0 Hz, 3H),1.11-1.04 (m, 1H), 0.57-0.47 (m, 2H), 0.41-0.36 (m, 1H), 0.34-0.29 (m,1H). LC-MS m/z: 342.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.14min.

(R)-5-(3-Cyano-5-methylthiophen-2-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure B*, methyl 5-methylthiophene-3-carboxylate(5.0 g, 32.0 mmol) afforded 5-methylthiophene-3-carboxylic acid as awhite solid (4.2 g, 92%), which was used directly in the next step.LC-MS m/z: no signal; t_(R)=0.75 min.

To a solution of 5-methylthiophene-3-carboxylic acid (1.42 g, 10.0 mmol)in HOAc (15 mL) was added a solution of Br₂ (1.6 g, 10.0 mmol) in HOAc(10 mL) dropwise. The reaction was stirred at RT for 1 h, and quenchedwith water (100 mL). The resulting precipitate was filtered and dried invacuo to afford 2-bromo-5-methylthiophene-3-carboxylic acid (2.0 g, 90%)as a white solid. LC-MS m/z: no signal; t_(R)=1.15 min.

Following general procedure A, 2-bromo-5-methylthiophene-3-carboxylicacid (2.0 g, 9.05 mmol), and NH₄Cl afforded2-bromo-5-methylthiophene-3-carboxamide as a grey solid (1.2 g, 59%).LC-MS m/z: 220.1 [M+H]⁺. t_(R)=1.45 min.

A mixture of 2-bromo-5-methylthiophene-3-carboxamide (1.17 g, 5.3 mmol),TFAA (1.45 g, 6.9 mmol) and TEA (1.34 g, 13.25 mmol) in DCM (15 mL) wasstirred at RT for 1 h, and partitioned between CH₂Cl₂ (50 mL) andsaturated NaHCO₃ (20 mL). The organic layer was dried over anhydrousNa₂SO₄ and filtered. The filtrate was concentrated in vacuo to afford2-bromo-5-methylthiophene-3-carbonitrile (1.25 g, 100%) as a brownsolid. LC-MS m/z: no signal; t_(R)=1.80 min.

Following general procedure E*,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.23 mmol) and 2-bromo-5-methylthiophene-3-carbonitrile affordedthe title compound (10 mg, 10%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.72 (s, 1H), 7.98 (d, J=9.6 Hz, 1H), 7.66 (s, 1H), 7.49 (s,1H), 5.04-4.99 (m, 1H), 2.87 (s, 3H), 2.59 (s, 3H), 1.46 (d, J=7.2 Hz,3H). LC-MS m/z: 394.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.94min.

(S)-5-(3-Cyano-5-methylthiophen-2-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(113 mg, 0.37 mmol) and 2-bromo-5-methylthiophene-3-carbonitrileafforded the title compound (35 mg, 28%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.72 (s, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.65 (s, 1H), 7.49(d, J=1.0 Hz, 1H), 5.05-4.98 (m, 1H), 2.87 (s, 3H), 2.59 (d, J=1.0 Hz,3H), 1.46 (d, J=7.0 Hz, 3H). LC-MS m/z: 394.1 [M+H]⁺. HPLC: Purity (214nm): 97%; t_(R)=8.92 min.

(R)-5-(2-Cyano-5-fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileafforded the title compound (33 mg, 32%) as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.77 (s, 1H), 8.26 (dd, J=8.5 Hz, 5.5 Hz, 1H), 8.11 (d,J=9.5 Hz, 1H), 8.08 (dd, J=9.5 Hz, 2.5 Hz, 1H), 7.88 (s, 1H), 7.70 (td,J=8.0 Hz, 2.5 Hz, 1H), 5.03-4.98 (m, 1H), 2.89 (s, 3H), 1.44 (d, J=7.0Hz, 3H). LC-MS m/z: 392.0 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.33min.

(S)-5-(2-Cyano-5-fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileafforded the title compound (37 mg, 37%) as a white solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.77 (s, 1H), 8.26 (dd, J=8.5 Hz, 5.5 Hz, 1H), 8.11 (d,J=9.5 Hz, 1H), 8.08 (dd, J=9.5 Hz, 2.5 Hz, 1H), 7.88 (s, 1H), 7.70 (td,J=8.0 Hz, 2.5 Hz, 1H), 5.03-4.98 (m, 1H), 2.89 (s, 3H), 1.44 (d, J=7.0Hz, 3H). LC-MS m/z: 392.0 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.33min.

(R)-5-(5-Cyano-2-fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileafforded the title compound (35.4 mg, 35%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.58 (dd, J=7.5 Hz, 2.0 Hz, 1H), 8.42 (d,J=9.5 Hz, 1H), 8.18 (ddd, J=9.0 Hz, 4.5 Hz, 2.0 Hz, 1H), 7.82 (s, 1H),7.75 (dd, J=11.0 Hz, 8.5 Hz, 1H), 5.00-4.92 (m, 1H), 2.89 (s, 3H), 1.41(d, J=7.0 Hz, 3H). LC-MS m/z: 392.1 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=8.30 min.

(S)-5-(5-Cyano-2-fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.26 mmol) and4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrileafforded the title compound (41 mg, 40%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.58 (dd, J=7.5 Hz, 2.0 Hz, 1H), 8.42 (d,J=9.5 Hz, 1H), 8.18 (ddd, J=9.0 Hz, 4.5 Hz, 2.0 Hz, 1H), 7.82 (s, 1H),7.75 (dd, J=11.0 Hz, 8.5 Hz, 1H), 5.00-4.92 (m, 1H), 2.89 (s, 3H), 1.41(d, J=7.0 Hz, 3H). LC-MS m/z: 392.1 [M+H]⁺. HPLC Purity (214 nm): >99%;t_(R)=8.26 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(4-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 3-bromo-4-(trifluoromethyl)pyridine afforded thetitle compound (5.7 mg, 5%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄):δ 8.85 (s, 1H), 8.82 (d, J=5.0 Hz, 1H), 8.52 (s, 1H), 8.19 (d, J=9.5 Hz,1H), 7.78 (d, J=5.5 Hz, 1H), 7.30 (s, 1H), 4.10-4.05 (m, 1H), 2.78 (s,3H), 0.97-0.91 (m, 1H), 0.57-0.51 (m, 1H), 0.39-0.33 (m, 2H), 0.21-0.16(m, 1H). LC-MS m/z: 444.1 [M+H]⁺. HPLC Purity (214 nm): 96.4%;t_(R)=8.44 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(4-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 3-bromo-4-(trifluoromethyl)pyridine afforded thetitle compound (2.1 mg, 2%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄):δ 8.85 (s, 1H), 8.82 (d, J=5.0 Hz, 1H), 8.52 (s, 1H), 8.19 (d, J=9.5 Hz,1H), 7.78 (d, J=5.5 Hz, 1H), 7.30 (s, 1H), 4.10-4.05 (m, 1H), 2.78 (s,3H), 0.97-0.91 (m, 1H), 0.57-0.51 (m, 1H), 0.39-0.33 (m, 2H), 0.21-0.16(m, 1H). LC-MS m/z: 444.1 [M+H]⁺. HPLC Purity (214 nm): 96.4%;t_(R)=8.44 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.150 mmol) and 2-(trifluoromethyl) pyridin-3-ylboronic acidafforded the title compound (22 mg, 33%) as a white solid. ¹H NMR (500MHz, MeOD-d₄) δ 8.72 (d, J=8.0 Hz, 1H), 8.70 (s, 1H), 8.32 (t, J=8.0 Hz,1H), 8.23 (d, J=0.5 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 4.45-4.42 (m, 1H),3.00 (d, J=0.5 Hz, 3H), 1.41-1.37 (m, 1H), 0.84-0.80 (m, 1H), 0.70-0.61(m, 2H), 0.57-0.51 (m, 1H). LC-MS m/z: 444.1 [M+H]⁺. HPLC: Purity (214nm): 98.97%; t_(R)=9.70 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(2-(trifluoromethyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.150 mmol) and 2-(trifluoromethyl) pyridin-3-ylboronic acidafforded the title compound (21 mg, 31%) as a white solid. ¹H NMR (500MHz, MeOD-d₄) δ 8.72 (d, J=8.0 Hz, 1H), 8.70 (s, 1H), 8.32 (t, J=8.0 Hz,1H), 8.23 (d, J=0.5 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 4.45-4.42 (m, 1H),3.00 (d, J=0.5 Hz, 3H), 1.41-1.37 (m, 1H), 0.84-0.80 (m, 1H), 0.70-0.61(m, 2H), 0.57-0.51 (m, 1H). LC-MS m/z: 444.1 [M+H]⁺. HPLC: Purity (214nm): 98.97%; t_(R)=9.70 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(3,4,4-trimethyl-2-oxoimidazolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(33 mg, 0.1 mmol) and 1,5,5-trimethylimidazolidin-2-one afforded thetitle compound (8.9 mg, 21%) as a pale white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.43 (s, 1H), 8.21 (d, J=10.0 Hz, 1H), 8.08 (s, 1H),4.39-4.35 (m, 1H), 3.85 (d, J=10.8 Hz, 1H), 3.75 (d, J=10.8 Hz, 1H),2.78 (s, 3H), 2.74 (s, 3H), 1.34 (s, 3H), 1.33 (s, 3H), 1.28-1.24 (m,1H), 0.69-0.65 (m, 1H), 0.59-0.55 (m, 2H), 0.38-0.36 (m, 1H). LC-MS m/z:425.1 [M+H]⁺. HPLC: Purity (214 nm): 97.06%; t_(R)=8.44 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5,5-dimethyl-2-oxooxazolidin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure H,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(73 mg, 0.219 mmol) and 5,5-dimethyloxazolidin-2-one afforded the titlecompound (22 mg, 25%) as a white solid. 1H NMR (500 MHz, DMSO-d₆) δ 8.54(s, 1H), 8.13 (d, J=9.5 Hz, 1H), 7.94 (s, 1H), 4.36-4.31 (m, 1H), 4.08(d, J=10.0 Hz, 1H), 3.98 (d, J=10.0 Hz, 1H), 2.80 (s, 3H), 1.54 (s, 6H),1.31-1.28 (m, 1H), 0.70-0.66 (m, 1H), 0.61-0.55 (m, 2H), 0.38-0.34 (m,1H). LC-MS m/z: 412.2 [M+H]⁺. HPLC: Purity (254 nm): >99%; t_(R)=8.42min.

(R)-5-(4-Fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.16 mmol) and 4-fluorophenylboronic acid afforded the titlecompound (18 mg, 30%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.66(s, 1H), 8.46 (d, J=9.2 Hz, 1H), 8.30 (dd, J=8.8 Hz, 5.2 Hz, 1H), 7.96(s, 1H), 7.50 (t, J=8.8 Hz, 1H), 5.01-4.94 (m, 1H), 2.86 (s, 3H), 1.46(d, J=6.8 Hz, 3H). LC-MS m/z: 367.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.98 min.

(S)-5-(4-Fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.21 mmol) and 4-fluorophenylboronic acid afforded the titlecompound (61 mg, 70%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.66(s, 1H), 8.46 (d, J=9.2 Hz, 1H), 8.30 (dd, J=8.8 Hz, 5.2 Hz, 1H), 7.96(s, 1H), 7.50 (t, J=8.8 Hz, 1H), 5.01-4.94 (m, 1H), 2.86 (s, 3H), 1.46(d, J=6.8 Hz, 3H). LC-MS m/z: 367.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.98 min.

(R)-5-(3-Fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.16 mmol) and 3-fluorophenylboronic acid afforded the titlecompound (28 mg, 47%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.69(s, 1H), 8.48 (d, J=10.0 Hz, 1H), 8.10 (d, J=8.5 Hz, 1H), 8.06 (dt,J=10.0 Hz, 1.5 Hz, 1H), 8.01 (s, 1H), 7.72-7.67 (m, 1H), 7.48 (td, J=8.5Hz, 2.5 Hz, 1H), 5.01-4.94 (m, 1H), 2.87 (s, 3H), 1.46 (d, J=6.8 Hz,3H). LC-MS m/z: 367.1 [M+H]⁺. HPLC: Purity (214 nm): 95%; t_(R)=8.96min.

(S)-5-(3-Fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.21 mmol) and 3-fluorophenylboronic acid afforded the titlecompound (36 mg, 40%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69(s, 1H), 8.48 (d, J=9.2 Hz, 1H), 8.10 (d, J=8.4 Hz, 1H), 8.06 (dt,J=10.8 Hz, 1.2 Hz, 1H), 8.01 (s, 1H), 7.72-7.67 (m, 1H), 7.48 (td, J=8.4Hz, 2.4 Hz, 1H), 5.01-4.94 (m, 1H), 2.87 (s, 3H), 1.46 (d, J=6.8 Hz,3H). LC-MS m/z: 367.1 [M+H]⁺. HPLC: Purity (214 nm): 95%; t_(R)=8.96min.

(R)-5-(5-Cyanopyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 5-cyanopyridin-3-ylboronic acid afforded thetitle compound (24 mg, 33%) as a white solid. 1H NMR (400 MHz, DMSO-d₆)δ 9.66 (d, J=2.0 Hz, 1H), 9.24 (d, J=2.0 Hz, 1H), 9.06 (t, J=2.4 Hz,1H), 8.74 (s, 1H), 8.46 (d, J=9.6 Hz, 1H), 8.12 (s, 1H), 4.47-4.43 (m,1H), 2.89 (s, 3H), 1.36-1.30 (m, 1H), 0.73-0.67 (m, 1H), 0.62-0.55 (m,2H), 0.42-0.38 (m, 1H). LC-MS m/z: 401.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.03 min.

(S)-5-(5-Cyanopyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 5-cyanopyridin-3-ylboronic acid afforded thetitle compound (12 mg, 13%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆):9.56 (d, J=2.0 Hz, 1H), 8.81 (dd, J=8.0 Hz, 2.0 Hz, 1H), 8.76 (s, 1H),8.46 (d, J=9.5 Hz, 1H), 8.37 (d, J=8.5 Hz, 1H), 8.13 (s, 1H), 4.45-4.40(m, 1H), 2.91 (s, 3H), 1.35-1.30 (m, 1H), 0.72-0.67 (m, 1H), 0.65-0.56(m, 2H), 0.42-0.35 (m, 1H). LC-MS m/z: 401.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.29 min.

(R)-5-(2-Cyanopyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 2-cyanopyridin-3-ylboronic acid afforded thetitle compound (2 mg, 3.0%) as a yellow solid. 1H NMR (500 MHz,MeOD-d₄): δ 8.90 (dd, J=5.0 Hz, 2.0 Hz, 1H), 8.74 (s, 1H), 8.54 (dd,J=8.0 Hz, 1.5 Hz, 1H), 7.91 (dd, J=8.0 Hz, 4.5 Hz, 1H), 7.70 (d, J=0.5Hz, 1H), 4.27-4.20 (m, 1H), 3.00 (s, 3H), 1.47-1.42 (m, 1H), 0.82-0.76(m, 1H), 0.63-0.58 (m, 2H), 0.46-0.41 (m, 1H). LC-MS m/z: 401.1 [M+H]⁺.HPLC Purity (214 nm): >99%; t_(R)=7.97 min.

(S)-5-(2-Cyanopyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 2-cyanopyridin-3-ylboronic acid afforded thetitle compound (2 mg, 3%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄):δ 8.90 (dd, J=5.0 Hz, 2.0 Hz, 1H), 8.74 (s, 1H), 8.54 (dd, J=8.0 Hz, 1.5Hz, 1H), 7.91 (dd, J=8.0 Hz, 4.5 Hz, 1H), 7.70 (d, J=0.5 Hz, 1H),4.27-4.20 (m, 1H), 3.00 (s, 3H), 1.47-1.42 (m, 1H), 0.82-0.76 (m, 1H),0.63-0.58 (m, 2H), 0.46-0.41 (m, 1H). LC-MS m/z: 401.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=7.97 min.

(R)-5-(6-Cyanopyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 6-cyanopyridin-3-ylboronic acid afforded thetitle compound (12.2 mg, 13%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆) δ 10.37 (d, J=1.5 Hz, 1H), 9.62 (dd, J=8.0 Hz, 2.0 Hz, 1H),9.57 (s, 1H), 9.26 (d, J=9.5 Hz, 1H), 9.17 (d, J=8.5 Hz, 1H), 8.94 (s,1H), 5.24-5.20 (m, 1H), 3.72 (s, 3H), 2.15-2.13 (m, 1H), 1.53-1.50 (m,1H), 1.43-1.38 (m, 2H), 1.20-1.18 (m, 1H). LC-MS m/z: 401.1 [M+H]⁺.HPLC: Purity (254 nm): >99%; t_(R)=8.28 min.

(S)-5-(6-Cyanopyridin-3-yl)-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and 6-cyanopyridin-3-ylboronic acid afforded thetitle compound (16 mg, 27%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄)δ 9.54 (d, J=1.5 Hz, 1H), 8.76 (dd, J=8.5 Hz, 2.5 Hz, 1H), 8.70 (s, 1H),8.13 (d, J=8.0 Hz, 1H), 7.89 (s, 1H), 4.43-4.39 (m, 1H), 2.99 (s, 3H),1.35-1.33 (m, 1H), 0.82-0.77 (m, 1H), 0.68-0.61 (m, 2H), 0.51-0.48 (m,1H). LC-MS m/z: 401.1 [M+H]⁺. HPLC: Purity (254 nm): 99.48%; t_(R)=8.30min.

5-(5-Cyanopyridin-3-yl)-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.17 mmol) and 5-cyanopyridin-3-ylboronic acid afforded thetitle compound (9 mg, 8%) as a yellow solid. ¹H NMR (500 MHz, DSMO-d₆):δ 9.68 (d, J=2.0 Hz, 1H), 9.23 (d, J=2.0 Hz, 1H), 9.06 (t, J=2.0 Hz,1H), 8.61 (s, 1H), 8.07 (s, 1H), 8.06 (s, 1H), 2.87 (s, 3H), 1.43-1.39(m, 1H), 1.38 (s, 6H), 0.51-0.50 (m, 4H). LC-MS m/z: 362.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=7.93 min.

5-(6-Cyanopyridin-3-yl)-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,5-chloro-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.17 mmol) and 6-cyanopyridin-3-ylboronic acid afforded thetitle compound (8 mg, 8%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆):δ 9.56 (d, J=1.5 Hz, 1H), 8.79 (dd, J=8.0 Hz, 2.0 Hz, 1H), 8.60 (s, 1H),8.34 (d, J=8.0 Hz, 1H), 8.05 (s, 1H), 8.04 (s, 1H), 2.87 (s, 3H),1.43-1.40 (m, 1H), 1.37 (s, 6H), 0.49-0.48 (m, 4H). LC-MS m/z: 362.1[M+H]⁺. HPLC Purity (214 nm): 97%; t_(R)=8.26 min.

5-(2-Cyanopyridin-3-yl)-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Using general procedure D,5-chloro-N-(2-cyclopropylpropan-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.24 mmol) and 2-cyanopyridin-3-ylboronic acid afforded thetitle compound (10 mg, 9%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆):δ 8.93 (dd, J=5.0 Hz 1.5 Hz, 1H), 8.66 (s, 1H), 8.51 (dd, J=8.0 Hz, 1.0Hz, 1H), 7.99 (dd, J=8.0 Hz, 4.5 Hz, 1H), 7.97 (s, 1H), 7.76 (s, 1H),3.34 (s, 3H), 2.89 (s, 3H), 1.50-1.44 (m, 1H), 0.42-0.37 (m, 2H),0.36-0.31 (m, 2H). LC-MS m/z: 361.1 [M+H]⁺. HPLC Purity (214 nm): 98%;t_(R)=8.26 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(2-fluoro-6-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 2-fluoro-6-methylpyridin-3-ylboronic acidafforded the title compound (35 mg, 48%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.48-8.53 (m, 2H), 7.77 (s, 1H), 7.53(dd, J=7.5 Hz, 1.0 Hz, 1H), 4.46-4.40 (m, 1H), 2.88 (s, 3H), 2.55 (s,3H), 1.26-1.22 (m, 1H), 0.72-0.66 (m, 1H), 0.60-0.55 (m, 2H), 0.39-0.35(m, 1H). LC-MS m/z: 408.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.83 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(2-fluoro-6-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 2-fluoro-6-methylpyridin-3-ylboronic acidafforded the title compound (45 mg, 46%) as a yellow solid. ¹H NMR (500MHz, DMSO-d₆): δ 8.71 (s, 1H), 8.48-8.53 (m, 2H), 7.77 (s, 1H), 7.53(dd, J=7.5 Hz, 1.0 Hz, 1H), 4.46-4.40 (m, 1H), 2.88 (s, 3H), 2.55 (s,3H), 1.26-1.22 (m, 1H), 0.72-0.66 (m, 1H), 0.60-0.55 (m, 2H), 0.39-0.35(m, 1H). LC-MS m/z: 408.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.86 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(2-fluoro-5-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(60 mg, 0.18 mmol) and 2-fluoro-5-methylpyridin-3-ylboronic acidafforded the title compound (43 mg, 58%) as a white solid. ¹H NMR (500MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.51 (d, J=9.5 Hz, 1H), 8.44 (dd, J=9.5Hz, 2.0 Hz, 1H), 8.29 (s, 1H), 7.79 (s, 1H), 4.50-4.46 (m, 1H), 2.89 (s,3H), 2.41 (s, 3H), 1.26-1.22 (m, 1H), 0.69-0.66 (m, 1H), 0.58-0.55 (m,2H), 0.40-0.36 (m, 1H). LC-MS m/z: 408.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.87 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(2-fluoro-5-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and 2-fluoro-5-methylpyridin-3-ylboronic acidafforded the title compound (45 mg, 73%) as a white solid. 1H NMR (500MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.51 (d, J=9.5 Hz, 1H), 8.44 (dd, J=9.5Hz, 2.0 Hz, 1H), 8.29 (s, 1H), 7.79 (s, 1H), 4.50-4.46 (m, 1H), 2.89 (s,3H), 2.41 (s, 3H), 1.26-1.22 (m, 1H), 0.69-0.66 (m, 1H), 0.58-0.55 (m,2H), 0.40-0.36 (m, 1H). LC-MS m/z: 408.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.87 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(2-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 2-methylpyridin-3-ylboronic acid afforded thetitle compound (36 mg, 39%) as a white solid. 1H NMR (500 MHz, DMSO-d₆):δ 8.71 (s, 1H), 8.63 (dd, J=5.0 Hz, 1.5 Hz, 1H), 8.34 (d, J=9.5 Hz, 1H),8.03 (dd, J=8.0 Hz, 1.5 Hz, 1H), 7.61 (s, 1H), 7.46 (dd, J=8.0 Hz, 5.0Hz, 1H), 4.41-4.37 (m, 1H), 2.87 (s, 3H), 2.71 (s, 3H), 1.17-1.14 (m,1H), 0.66-0.63 (m, 1H), 0.57-0.50 (m, 2H), 0.31-0.28 (m, 1H). LC-MS m/z:390.1 [M+H]⁺. HPLC: Purity (214 nm): 98%; t_(R)=7.75 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(2-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and 2-methylpyridin-3-ylboronic acid afforded thetitle compound (23 mg, 40%) as a white solid. ¹H NMR (400 MHz, CDCl₃): δ8.74 (s, 1H), 8.67 (dd, J=5.0 Hz, 1.5 Hz, 1H), 8.33 (d, J=9.5 Hz, 1H),7.86 (dd, J=8.0 Hz, 1.5 Hz, 1H), 7.33 (dd, J=8.0 Hz, 5.0 Hz, 1H), 7.05(d, J=1.5 Hz, 1H), 4.41-4.36 (m, 1H), 2.93 (s, 3H), 2.77 (s, 3H),1.16-1.09 (m, 1H), 0.72-0.66 (m, 1H), 0.57-0.49 (m, 2H), 0.46-0.41 (m,1H). LC-MS m/z: 390.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=7.72min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-fluoro-2-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of n-BuLi/THF (1.45 mL, 2.5 mol/L) in THF (5 mL) was addeda solution of 3-bromo-2-chloro-5-fluoropyridine (630 mg, 3.0 mmol) inTHF (5 mL) dropwise at −78° C. The reaction mixture was stirred at −78°C. for another 30 minutes, followed by the addition of B(OiPr)₃ (677 mg,3.6 mmol) in THF (2 mL). The mixture was stirred at −78° C. for another2 h, and quenched with 5% NaOH aqueous solution (10 mL). The mixture wasacidified to pH 1-2 with dilute aqueous HCl solution, and extracted withEA (60 mL×3). The combined organic phases were dried over anhydrousMgSO₄ and filtered. The filtrate was concentrated in vacuo to afford2-chloro-5-fluoropyridin-3-ylboronic acid (1.5 g, crude) as grey oil,which was used in the next step without further purifications. LC-MSm/z: 176.1 [M+H]⁺. t_(R)=0.64 min.

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (800 mg, 3.34mmol) and 2-chloro-5-fluoropyridin-3-ylboronic acid afforded ethyl5-(2-chloro-5-fluoropyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(260 mg, 23%) as a grey solid. LC-MS m/z: 335.1 [M+H]⁺. t_(R)=1.75 min.

A solution of ethyl5-(2-chloro-5-fluoropyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(180 mg, 0.53 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane(203 mg, 1.61 mmol), K₂CO₃ (190 mg, 1.38 mmol), andbis(di-tert-butyl(4-dimethylaminophenyl)phosphine) dichloropalladium(II) (75 mg, 0.106 mmol) in DMF (10 mL) was stirred at 90° C. for 16hours under N₂, poured into H₂O (30 mL), and extracted with EA (80mL×3). The combined organic phases were dried over anhydrous MgSO₄ andfiltered. The filtrate was concentrated in vacuo and the residue waspurified by silica gel column chromatography (PE/EA=9/1) to afford ethyl5-(5-fluoro-2-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(146 mg, 88%) as a red solid. LC-MS m/z: 315.1 [M+H]⁺. t_(R)=1.67 min.

Following general procedure B*, ethyl5-(5-fluoro-2-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(144 mg, 0.45 mmol) afforded5-(5-fluoro-2-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (72 mg, 56%) as a grey solid. LC-MS m/z: 287.1 [M+H]⁺. t_(R)=1.11min.

Following general procedure A,5-(5-fluoro-2-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (20 mg, 0.07 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (6.4 mg, 22%) as an off-whitesolid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.74 (s, 1H), 8.67 (d, J=3.0 Hz,1H), 8.31 (d, J=9.5 Hz, 1H), 8.03 (dd, J=9.5 Hz, 3.0 Hz, 1H), 7.67 (s,1H), 4.44-4.35 (m, 1H), 2.88 (s, 3H), 2.70 (s, 3H), 1.21-1.14 (m, 1H),0.68-0.64 (m, 1H), 0.60-0.49 (m, 2H), 0.33-0.28 (m, 1H). LC-MS m/z:408.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.36 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-fluoro-2-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(5-fluoro-2-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (20 mg, 0.07 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (6.4 mg, 22%) as an off-whitesolid. ¹H NMR (500 MHz, DMSO-d₆): δ 8.74 (s, 1H), 8.67 (d, J=3.0 Hz,1H), 8.31 (d, J=9.5 Hz, 1H), 8.03 (dd, J=9.5 Hz, 3.0 Hz, 1H), 7.67 (s,1H), 4.44-4.35 (m, 1H), 2.88 (s, 3H), 2.70 (s, 3H), 1.21-1.14 (m, 1H),0.68-0.64 (m, 1H), 0.60-0.49 (m, 2H), 0.33-0.28 (m, 1H). LC-MS m/z:408.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.36 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-fluoro-6-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A solution of 5-bromo-2-methylpyridin-3-amine (2 g, 10.69 mmol) andNOBF₄ (1.5 g, 12.83 mmol) in DCM (20 mL) was stirred at 20° C. for 16 h,and quenched with saturated NaHCO₃ (10 mL) to pH=8. The mixture wasdiluted with DCM (20 mL) and washed with H₂O (10 mL×3). The organicphase was dried over anhydrous Na₂SO₄, filtered, concentrated in vacuo,and the residue was purified by silica gel flash chromatography (EA:PE;0 to 5%) to afford 5-bromo-3-fluoro-2-methylpyridine (500 mg, 40%) as ayellow solid. LC-MS m/z: 191.1 [M+H]⁺. LC-MS Purity (214 nm): >88%;t_(R)=1.24 min.

Following general procedure E*,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 5-bromo-3-fluoro-2-methylpyridine afforded thetitle compound (17 mg, 17%) as a yellow solid. ¹H NMR (500 MHz,DMSO-d₆): δ 9.18 (s, 1H), 8.70 (s, 1H), 8.48 (d, J=10.0 Hz, 1H), 8.38(dd, J=10.5 Hz, 1.5 Hz, 1H), 8.05 (s, 1H), 4.50-4.43 (m, 1H), 2.87 (s,3H), 2.57 (d, J=3.0 Hz, 3H), 1.31-1.25 (m, 1H), 0.72-0.66 (m, 1H),0.61-0.55 (m, 2H), 0.41-0.37 (m, 1H). LC-MS m/z: 408.1 [M+H]⁺. HPLCPurity (214 nm): >99%; t_(R)=8.66 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-fluoro-6-methylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(80 mg, 0.24 mmol) and 5-bromo-3-fluoro-2-methylpyridine afforded thetitle compound (8.8 mg, 9%) as a yellow solid. ¹H NMR (500 MHz,MeOD-d₄): δ 9.14 (s, 1H), 8.66 (s, 1H), 8.34 (dd, J=10.5 Hz, 2.0 Hz,1H), 7.83 (s, 1H), 4.46-4.43 (m, 1H), 2.96 (s, 3H), 2.64 (d, J=3.0 Hz,3H), 1.34-1.30 (m, 1H), 0.81-0.78 (m, 1H), 0.69-0.60 (m, 2H), 0.59-0.50(m, 1H). LC-MS m/z: 408.1 [M+H]⁺. HPLC Purity (214 nm): >99%; t_(R)=8.70min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluorethyl)-7-methyl-5-(6-methylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and 2-methyl-6-(tributylstannyl)pyridine afforded thetitle compound (38 mg, 65%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆):δ 8.69 (s, 1H), 8.56 (d, J=10.0 Hz, 1H), 8.22 (d, J=7.5 Hz, 1H), 8.16(d, J=1.0 Hz, 1H), 8.00 (t, J=7.5 Hz, 1H), 7.50 (d, J=7.5 Hz, 1H),4.48-4.44 (m, 1H), 2.91 (s, 3H), 1.36-1.32 (m, 1H), 0.72-0.66 (m, 1H),0.63-0.57 (m, 2H), 0.45-0.39 (m, 1H). LC-MS m/z: 390.1 [M+H]⁺. HPLC:Purity (214 nm): 98.31%; t_(R)=9.53 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-ethynylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D, ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (721 mg, 2.97mmmol) and 5-bromopyridin-3-ylboronic acid afforded ethyl5-(5-bromopyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(200 mg, 22%) as a yellow solid. LC-MS m/z: 361.0 [M+H]⁺. t_(R)=6.92min.

To a solution of ethyl5-(5-bromopyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(150 mg, 0.41 mmol) in CH₃CN (5 mL) was added ethynyltrimethylsilane (61mg, 0.62 mmol), Et₃N (84 mg, 0.83 mmol), Pd(PPh₃)₂Cl₂ (29 mg, 0.04mmol), CuI (4.5 mg, 0.04 mmol) and PPh₃ (33 mg, 0.3 mmol). The mixturewas stirred for 18 h at 80° C. under N₂, and concentrated in vacuo. Theresidue was purified by silica gel column chromatography(PE:EA=10:1˜2:1) to afford ethyl7-methyl-5-(5-((trimethylsilyl)ethynyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(100 mg, 63%) as a yellow solid. LC-MS m/z: 390.0 [M+H]⁺, t_(R)=1.60 min

To a solution of ethyl7-methyl-5-(5-((trimethylsilyl)ethynyl)pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate(150 mg, 0.39 mmol) in THF/MeOH/H₂O (6 mL, 2/2/2) was added LiOH.2H₂O(71 mg, 1.19 mmol). The mixture was stirred for 18 h at 30° C., andextracted with DCM (20 mL×3). The organic phases were dried overanhydrous Na₂SO₄ and filtered. The filtrate was concentrated in vacuo toafford5-(5-ethynylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (100 mg, 91%) as a yellow solid. LC-MS m/z: 279.1 [M+H]⁺,t_(R)=1.01 min.

Following general procedure A,5-(5-ethynylpyridin-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (100 mg, 0.36 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (60 mg, 42%) as a white solid.¹H NMR (500 MHz, DMSO-d₆): δ 9.42 (d, J=2.0 Hz, 1H), 8.88 (d, J=1.5 Hz,1H), 8.71 (s, 1H), 8.69 (t, J=2.0 Hz, 1H), 8.49 (d, J=9.0 Hz, 1H), 8.11(s, 1H), 4.61 (s, 1H), 4.51-4.46 (m, 1H), 2.88 (s, 3H), 1.29-1.25 (m,1H), 0.71-0.67 (m, 1H), 0.60-0.57 (m, 2H), 0.42-0.39 (m, 1H). LC-MS m/z:400.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.36 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(6-(methoxymethoxy)pyridin-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.15 mmol) and 2-bromo-6-(methoxymethoxy)pyridine (69 mg, 0.32mmol) afforded the title compound (18 mg, 27%) as a white solid. ¹H NMR(500 MHz, MeOD-d₄) δ 8.65 (s, 1H), 8.15-8.12 (m, 2H), 7.97 (t, J=7.5 Hz,1H), 7.06 (d, J=8.5 Hz, 1H), 5.73 (s, 2H), 4.47-4.44 (m, 1H), 3.58 (s,3H), 2.96 (s, 3H), 1.38-1.33 (m, 1H), 0.81-0.77 (m, 1H), 0.70-0.65 (m,1H), 0.63-0.58 (m, 1H), 0.56-0.51 (m, 1H). LC-MS m/z: 436.1 [M+H]⁺,HPLC: Purity (214 nm): >99%; t_(R)=9.30 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3,5-dimethylisothiazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,(R)—N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(tributylstannyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.12 mmol) and 4-iodo-3,5-dimethylisothiazole afforded the titlecompound (7.0 mg, 14%) as a white solid. 1H NMR (500 MHz, DMSO-d₆) δ8.70 (s, 1H), 8.28 (d, J=9.5 Hz, 1H), 7.49 (s, 1H), 4.36-4.31 (m, 1H),2.86 (s, 3H), 2.68 (s, 3H), 2.55 (s, 3H), 1.20-1.15 (m, 1H), 0.69-0.65(m, 1H), 0.61-0.57 (m, 1H), 0.54-0.50 (m, 1H), 0.31-0.26 (m, 1H). LC-MSm/z: 410.1 [M+H]+. HPLC: Purity (214 nm): >99%; t_(R)=9.90 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(3,5-dimethylisothiazol-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure F,(S)—N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(tributylstannyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide(70 mg, 0.12 mmol) and 4-iodo-3,5-dimethylisothiazole afforded the titlecompound (4.0 mg, 10%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.70 (s, 1H), 8.28 (d, J=9.5 Hz, 1H), 7.49 (s, 1H), 4.36-4.31 (m, 1H),2.86 (s, 3H), 2.68 (s, 3H), 2.55 (s, 3H), 1.20-1.15 (m, 1H), 0.69-0.65(m, 1H), 0.61-0.57 (m, 1H), 0.54-0.50 (m, 1H), 0.31-0.26 (m, 1H). LC-MSm/z: 410.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=9.90 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(5-methylisothiazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and 4-bromo-5-methylisothiazole afforded the titlecompound (18 mg, 20%) as a white solid. ¹H NMR (500 MHz, MeOD-d₄) δ 9.01(s, 1H), 8.63 (s, 1H), 7.61 (s, 1H), 4.34-4.28 (m, 1H), 2.98 (s, 3H),2.92 (s, 3H), 1.26-1.21 (m, 1H), 0.81-0.77 (m, 1H), 0.66-0.56 (m, 2H),0.45-0.41 (m, 1H). LC-MS m/z: 396.0 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.80 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(5-methylisothiazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol) and 4-bromo-5-methylisothiazole afforded the titlecompound (1.8 mg, 2.0%) as a white solid. 1H NMR (500 MHz, MeOD-d₄) δ9.01 (s, 1H), 8.63 (s, 1H), 7.61 (s, 1H), 4.34-4.28 (m, 1H), 2.98 (s,3H), 2.92 (s, 3H), 1.26-1.21 (m, 1H), 0.81-0.77 (m, 1H), 0.66-0.56 (m,2H), 0.45-0.41 (m, 1H). LC-MS m/z: 396.0 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.80 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(3-methylisothiazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(110 mg, 0.33 mmol) and 4-bromo-3-methylisothiazole afforded the titlecompound (35 mg, 26%) as a yellow solid. 1H NMR (500 MHz, DMSO-d₆): δ9.78 (s, 1H), 8.67 (s, 1H), 8.25 (d, J=9.5 Hz, 1H), 7.76 (s, 1H),4.32-4.28 (m, 1H), 2.85 (s, 3H), 2.84 (s, 3H), 1.23-1.18 (m, 1H),0.74-0.62 (m, 2H), 0.61-0.56 (m, 1H), 0.34-0.28 (m, 1H). LC-MS m/z:396.0 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.54 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-7-methyl-5-(3-methylisothiazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(110 mg, 0.33 mmol) and 4-bromo-3-methylisothiazole afforded the titlecompound (75 mg, 58%) as a yellow solid. 1H NMR (500 MHz, DMSO-d₆): δ9.78 (s, 1H), 8.67 (s, 1H), 8.25 (d, J=9.5 Hz, 1H), 7.76 (s, 1H),4.32-4.28 (m, 1H), 2.85 (s, 3H), 2.84 (s, 3H), 1.23-1.18 (m, 1H),0.74-0.62 (m, 2H), 0.61-0.56 (m, 1H), 0.34-0.28 (m, 1H). LC-MS m/z:396.0 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.54 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-iso-propyl-1,3,4-oxadiazol-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of(R)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.30 mmol), Pd(PPh₃)₂Cl₂.CH₂Cl₂ (25 mg, 0.03 mmol) and Et₃N(100 mg, 0.9 mmol) in MeOH (10 mL) was stirred at 65° C. for 6 h under10 atm of CO. The reaction mixture was filtered and concentrated invacuo to give crude(R)-3-((1-cyclopropyl-2,2,2-trifluoroethyl)carbamoyl)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid (100 mg, 93%) as a yellow solid. LC-MS m/z: 343.1 [M+H]⁺, Purity(214 nm): 90%; t_(R)=1.23 min.

A mixture of(R)-3-((1-cyclopropyl-2,2,2-trifluoroethyl)carbamoyl)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid (100 mg, 0.30 mmol) and thionyl chloride (100 mg, 0.9 mmol) in MeOH(10 mL) was stirred at 65° C. for 1 h. The reaction mixture wasconcentrated in vacuo and purified by silica gel chromatography (EA) togive methyl(R)-3-((1-cyclopropyl-2,2,2-trifluoroethyl)carbamoyl)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(70 mg, 67%) as a yellow solid. LC-MS m/z: 357.1 [M+H]⁺, Purity (214nm): 93%; t_(R)=1.76 min.

A mixture of methyl(R)-3-((1-cyclopropyl-2,2,2-trifluoroethyl)carbamoyl)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(55 mg, 0.15 mmol) and hydrazine hydrate (55 mg, 1.5 mmol) in EtOH (10mL) was stirred at RT for 1 h. The reaction mixture was concentrated invacuo to give crude(R)—N-(1-cyclopropyl-2,2,2-trifluoroethyl)-5-(hydrazinecarbonyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 97%) as a yellow solid. LC-MS m/z: 357.1 [M+H]⁺, Purity (214nm): 90%; t_(R)=1.46 min.

A mixture of(R)—N-(1-cyclopropyl-2,2,2-trifluoroethyl)-5-(hydrazinecarbonyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(50 mg, 0.14 mmol), 1,1,1-trimethoxy-2-methylpropane (50 mg, 0.28 mmol)in HOAc (5 mL) was stirred at RT for 4 h. Then EA (50 mL) was added andwashed with saturated NaHCO₃ (50 mL) and brine (50 mL). The organiclayer was dried over anhydrous Na₂SO₄ and concentrated in vacuo. Theresidue was purified by preparative HPLC to give the title compound (10mg, 15%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.80 (s, 1H),8.41 (d, J=9.5 Hz, 1H), 8.00 (s, 1H), 4.65-4.60 (m, 1H), 3.42-3.36 (m,1H), 2.92 (s, 3H), 3.41 (d, J=7.0 Hz, 6H), 1.26-1.20 (m, 1H), 0.69-0.65(m, 1H), 0.62-0.57 (m, 1H) 0.53-0.49 (m, 2H). LC-MS m/z: 409.1 [M+H]⁺,HPLC: Purity (214 nm): >99%; t_(R)=8.52 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-iso-propyl-1,3,4-oxadiazol-2-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(150 mg, 0.45 mmol), Pd(PPh₃)₂Cl₂.CH₂Cl₂ (37 mg, 0.05 mmol), Et₃N (138mg, 1.35 mmol) in MeOH (10 mL) was stirred at 65° C. for 6 h under 10atm of CO. The reaction mixture was filtered and concentrated in vacuoto give crude(S)-3-((1-cyclopropyl-2,2,2-trifluoroethyl)carbamoyl)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid (150 mg, 93%) as a yellow solid. LC-MS m/z: 343.1 [M+H]⁺, Purity(214 nm): 95%; t_(R)=1.23 min.

A mixture of(S)-3-((1-cyclopropyl-2,2,2-trifluoroethyl)carbamoyl)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylicacid (150 mg, 0.45 mmol) and thionyl chloride (145 mg, 0.9 mmol) in MeOH(10 mL) was stirred at 65° C. for 1 h. The reaction mixture wasconcentrated in vacuo and purified by silica gel chromatography (EA) togive methyl(S)-3-((1-cyclopropyl-2,2,2-trifluoroethyl)carbamoyl)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(120 mg, 75%) as a white solid. LC-MS m/z: 357.1 [M+H]⁺, Purity (214nm): 92%; t_(R)=1.76 min.

A mixture of methyl(S)-3-((1-cyclopropyl-2,2,2-trifluoroethyl)carbamoyl)-7-methylpyrazolo[1,5-a]pyrimidine-5-carboxylate(120 mg, 0.34 mmol) and hydrazine hydrate (120 mg, 3.40 mmol) in EtOH(10 mL) was stirred at RT for 1 h. The reaction mixture was concentratedin vacuo to give crude(S)—N-(1-cyclopropyl-2,2,2-trifluoroethyl)-5-(hydrazinecarbonyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 80%) as a yellow solid. LC-MS m/z: 357.1 [M+H]⁺, Purity (214nm): 97%, t_(R)=1.46 min.

A mixture of(S)—N-(1-cyclopropyl-2,2,2-trifluoroethyl)-5-(hydrazinecarbonyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.28 mmol), 1,1,1-trimethoxy-2-methylpropane (100 mg, 0.56mmol) in HOAc (5 mL) was stirred at RT for 16 h. Then EA (50 mL) wasadded and washed with saturated NaHCO₃ (50 mL) and brine (50 mL). Theorganic layer was dried over anhydrous Na₂SO₄ and concentrated in vacuo.The residue was purified by preparative HPLC to give the title compound(10 mg, 8.0%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.80 (s,1H), 8.41 (d, J=9.5 Hz, 1H), 8.00 (s, 1H), 4.65-4.60 (m, 1H), 3.42-3.36(m, 1H), 2.92 (s, 3H), 3.41 (d, J=7.0 Hz, 6H), 1.27-1.21 (m, 1H),0.70-0.64 (m, 1H), 0.61-0.56 (m, 1H) 0.54-0.49 (m, 2H). LC-MS m/z: 409.1[M+H]⁺, HPLC: Purity (214 nm): >99%; t_(R)=8.52 min.

(R)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-iso-propyl-1,2,4-oxadiazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

A mixture of ethyl5-chloro-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (2 g, 8.34mmol), Pd₂(dba)₃ (480 mg, 0.834 mmol), dppf (924 mg, 1.67 mmol), andZn(CN)₂ (1.96 g, 16.73 mmol) was purged with N₂, followed by theaddition of DMF (25 mL). The suspension was purged with N₂, heated at90° C. for 4 h and then cooled to RT and filtered. The filtrate wasdiluted with water (100 mL), and extracted with EA (80 mL×3). Theorganic phases were washed with H₂O (50 mL×3), brine (100 mL), driedover anhydrous Na₂SO₄, and filtered. The filtrate was concentrated invacuo, and the residue was purified by silica gel chromatography(PE/EA=6/4, v/v) to afford ethyl5-cyano-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (1.50 g, 78%) asa white solid. LC-MS m/z: 231.1 [M+H].

A mixture of ethyl5-cyano-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (500 mg, 2.17mmol), hydroxylamine hydrochloride (308 mg, 4.34 mmol), and Et₃N (657mg, 6.51 mmol) in 10 mL of DMF was stirred at 90° C. for 17 h anddiluted with water (40 mL). The suspension was filtered to afford ethyl5-(N-hydroxycarbamimidoyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(524 mg, 91%) as a white solid. LC-MS m/z: 264.1 [M+H]⁺.

A mixture of ethyl5-(N-hydroxycarbamimidoyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(514 g, 1.95 mmol), iso-butyric anhydride (926 mg, 5.86 mmol) in 15 mLof DCM was stirred at RT for 1 hour, and concentrated in vacuo. Theresidue was diluted with 15 mL of DMSO and heated at 90° C. for 24 h.The reaction mixture was diluted with H₂O (80 mL), and the suspensionwas filtered to afford ethyl5-(5-iso-propyl-1,2,4-oxadiazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(390 mg, 96%) as a white solid. LC-MS m/z: 316.1 [M+H]⁺.

Following general procedure B*, ethyl5-(5-iso-propyl-1,2,4-oxadiazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate(580 mg, 1.84 mmol) afforded5-(5-iso-propyl-1,2,4-oxadiazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (529 mg, 100%) as a brown solid. LC-MS m/z: 288.1 [M+H]⁺.

Following general procedure A,5-(5-iso-propyl-1,2,4-oxadiazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (110 mg, 0.38 mmol) and (R)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (39 mg, 25%) as a gray solid.¹H NMR (500 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.52 (d, J=10.0 Hz, 1H), 7.89(s, 1H), 4.67-4.61 (m, 1H), 3.48-3.40 (m, 1H), 2.92 (s, 3H), 1.43 (d,J=7.0 Hz, 6H), 1.25-1.21 (m, 1H), 0.66-0.56 (m, 3H), 0.50-0.46 (m, 1H).LC-MS m/z: 409.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=9.26 min.

(S)—N-(1-Cyclopropyl-2,2,2-trifluoroethyl)-5-(5-iso-propyl-1,2,4-oxadiazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(5-iso-propyl-1,2,4-oxadiazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.10 mmol) and (S)-1-cyclopropyl-2,2,2-trifluoroethanaminehydrochloride afforded the title compound (4.7 mg, 11%) as a gray solid.¹H NMR (500 MHz, MeOD-d₄) δ 8.70 (s, 1H), 7.85 (s, 1H), 4.55-4.49 (m,1H), 3.44-3.39 (m, 1H), 2.96 (s, 3H), 1.51 (d, J=7.0 Hz, 6H), 1.38-1.32(m, 1H), 0.74-0.60 (m, 3H), 0.54-0.51 (m, 1H). LC-MS m/z: 409.1 [M+H]⁺.HPLC: Purity (214 nm): >99%; t_(R)=9.26 min.

(S)-5-Cyano-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of(S)-5-chloro-N-(1-cyclopropyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(150 mg, 0.45 mmol) in 3 mL dioxane were added Zn(CN)₂ (158 mg, 1.355mmol) and Pd(PPh₃)₄(52 mg, 0.045 mmol) at RT under N₂ atmosphere. Themixture was stirred at 110° C. for 15 h, then cooled and concentratedand purified by silica gel chromatography (EA:PE=1:1) to give the titlecompound (7 mg, 4.8%) as a yellow solid. ¹H NMR (500 MHz, MeOD-d₄) δ8.81 (s, 1H), 7.60 (s, 1H), 4.38-4.34 (m, 1H), 2.96 (s, 3H), 1.35-1.31(m, 1H), 0.81-0.78 (m, 1H), 0.70-0.67 (m, 1H), 0.62-0.59 (m, 1H),0.50-0.48 (m, 1H). LC-MS m/z: 339.1 [M+H]⁺. HPLC: Purity (214 nm): 100%;t_(R)=8.68 min.

(S)-5-(2-Cyano-5-fluorophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamideand (2-cyano-5-fluorophenyl)boronic acid afforded the title compound (55mg, 60%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H),8.25 (dd, J=8.5 Hz, 5.5 Hz, 1H), 8.10 (dd, J=10.0 Hz, 2.5 Hz, 1H), 8.01(d, J=8.0 Hz, 1H), 7.85 (s, 1H), 7.69 (td, J=8.5 Hz, J=2.5 Hz, 1H),3.55-3.52 (m, 1H), 2.89 (s, 3H), 1.29 (d, J=6.5 Hz, 1H), 1.12-1.09 (m,1H), 0.47-0.44 (m, 1H), 0.38-0.32 (m, 1H), 0.32-0.25 (m, 1H). LC-MS m/z:364.1 [M+H]⁺. HPLC: Purity (214 nm): 96%; t_(R)=8.20 min.

(S)-5-(2-Cyano-6-fluorophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamideand 2-bromo-3-fluorobenzonitrile afforded the title compound (22 mg,21%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (s, 1H), 8.03(d, J=7.5 Hz, 1H), 7.94 (d, J=8.0 Hz, 1H), 7.91-7.82 (m, 2H), 7.63 (d,J=3.0 Hz, 1H), 3.60-3.55 (m, 1H), 2.90 (s, 3H), 1.24 (d, J=6.5 Hz, 3H),1.03-0.99 (m, 1H), 0.45-0.41 (m, 1H), 0.37-0.31 (m, 2H), 0.26-0.24 (m,1H). LC-MS m/z: 364.2 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.05min.

(S)-5-(2-Cyano-3-fluorophenyl)-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-cyclopropylethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamideand (2-cyano-3-fluorophenyl)boronic acid afforded the title compound (46mg, 49%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (s, 1H),8.04-8.03 (m, 2H), 7.98 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.83-7.79 (m,1H), 3.55-3.54 (m, 1H), 2.89 (s, 3H), 1.29 (d, J=6.5 Hz, 1H), 1.11-1.09(m, 1H), 0.47-0.46 (m, 1H), 0.37-0.32 (m, 2H), 0.26-0.24 (m, 1H). LC-MSm/z: 364.1 [M+H]⁺. HPLC: Purity (214 nm): >99%; t_(R)=8.12 min.

(S)-5-(2-Cyano-3-fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure D,(S)-5-chloro-N-(1-methyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(79 mg, 0.26 mmol) and (2-cyano-3-fluorophenyl)boronic acid afforded thetitle compound (65 mg, 64%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆)δ 8.77 (s, 1H), 8.08 (d, J=9.5 Hz, 1H), 8.05-8.01 (m, 2H), 7.86 (s, 1H),7.82-7.78 (m, 1H), 5.01-4.99 (m, 1H), 2.91 (s, 3H), 1.44 (d, J=7.0 Hz,3H). LC-MS m/z: 392.0 [M+H]⁺. HPLC: Purity (214 nm): 97%; t_(R)=8.26min.

(S)-5-(2-Cyano-6-fluorophenyl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure E*,(S)-5-chloro-N-(1-methyl-2,2,2-trifluoroethyl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide(100 mg, 0.32 mmol) and 2-bromo-3-fluorobenzonitrile afforded the titlecompound (64 mg, 41%) as a white solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.79(s, 1H), 8.13 (d, J=9.5 Hz, 1H), 8.03 (d, J=7.5 Hz, 1H), 7.92-7.83 (m,2H), 7.68 (d, J=3.0 Hz, 1H), 4.98-4.94 (m, 1H), 2.91 (s, 3H), 1.39 (d,J=6.5 Hz, 3H). LC-MS m/z: 392.1 [M+H]⁺. HPLC: Purity (214 nm): >99%;t_(R)=8.22 min.

(S)-5-(5-iso-Propyl-1,2,4-oxadiazol-3-yl)-7-methyl-N-(1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(5-iso-propyl-1,2,4-oxadiazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.10 mmol) and (S)-1,1,1-trifluoropropan-2-amine (22 mg,0.15 mmol) afforded the title compound (6.5 mg, 15%) as a white solid.¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.54 (d, J=9.0 Hz, 1H), 7.88(d, J=1.0 Hz, 1H), 4.95 (q, J=8.0 Hz, 1H), 3.47-3.41 (m, 1H), 2.92 (s,3H), 1.43 (d, J=7.0 Hz, 9H). LC-MS m/z: 383.1 [M+H]⁺. HPLC: Purity (214nm): >99%; t_(R)=8.83 min.

(S)—N-(1-Cyclopropylethyl)-5-(5-iso-propyl-1,2,4-oxadiazol-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide

Following general procedure A,5-(5-iso-propyl-1,2,4-oxadiazol-3-yl)-7-methylpyrazolo[1,5-a]pyrimidine-3-carboxylicacid (30 mg, 0.10 mmol) and (S)-1-cyclopropylethan-1-amine afforded thetitle compound (8.8 mg, 23%) as a red solid. ¹H NMR (500 MHz, DMSO-d₆) δ8.69 (s, 1H), 8.14 (d, J=7.5 Hz, 1H), 7.84 (s, 1H), 3.77-3.73 (m, 1H),3.47-3.41 (m, 1H), 2.91 (s, 3H), 1.43 (d, J=7.0 Hz, 6H), 1.26 (d, J=6.5Hz, 3H), 1.03-0.98 (m, 1H), 0.50-0.42 (m, 3H), 0.29-0.27 (m, 1H). LC-MSm/z: 355.2 [M+H]⁺. HPLC: Purity (254 nm): 96%; t_(R)=8.73 min.

Example 2—Biological Activity Evaluation

The ability of exemplary compounds to activate glucocerebrosidase(Gcase) was measured. Experimental procedures and results are providedbelow.

Part I: Assay Procedure

A 484 μL aliquot of a 1.0 mg/mL solution of phosphatidylserine (PS)(Sigma P7769) in chloroform was evaporated under a stream of nitrogenfor 1 hour. The lipid film was dissolved over 4 minutes of vigorousvortexing in 40 mL of 176 mM K₂HPO₄/50 mM citric acid (pH 4.7)containing 7.5 μL of triton X-100, resulting in a mixed micellarpreparation with a composition of 0.32 mM triton and 0.37 mol % PS.4-Methylumbelliferyl-beta-D-glucopyranoside (ACROS-337025000) wasdissolved in the micellar solution to a final concentration of 2 mM foruse as the reaction substrate.

Test compounds were diluted to the desired concentrations withdimethylsulfoxide (DMSO) from 10 mM stocks, and 0.41 μL of the DMSOcompound mixture was added to 100 μL of micellar solution containing 10nM GCase and 100 nM saposin C (Enzo ALX-201-262-C050). Pre-incubationwas allowed to occur for 30 minutes at room temperature, after which thereaction was initiated by combining 25 μL of substrate solution with 25μL of compound/GCase/saposin mixture. The reaction proceeded for 15minutes at room temperature and was stopped by adding 150 μL of 1Mglycine, pH 12.5. The endpoint of the reaction was monitored bymeasuring fluorescence intensity (excitation: 365 nm; emission: 440 nm)on a SpectraMax i3 instrument (Molecular Devices). Test compounds werescreened at 1.0 and 0.1 μM final concentration, and subsequent 8-pointdose response curves were obtained using 3-fold dilutions from a maximumfinal concentration of 5 μM.

Part II: Results

Gcase activation values for tested compounds are provided in Tables 3A,3B, and 4 below, along with c Log P, PSA, and compound solubility inwater. For experiments in which the test compound was used at aconcentration of 1.0 μM, the symbol “+” indicates less than 30% Gcaseactivation; the symbol “++” indicates Gcase activation in the range of30% up to 60%; and the symbol “+++” indicates Gcase activation greaterthan 60%. For experiments in which the test compound was used at aconcentration of 0.1 μM, the symbol “*” indicates less than 10% Gcaseactivation; the symbol “**” indicates Gcase activation in the range of10% up to 20%; and the symbol “***” indicates greater than 20% Gcaseactivation.

TABLE 3A Compound Com- Solubility in Percent Gcase Activation poundWater 1 μM Test 0.1 μM Test No. Compound Structure cLogP PSA (μg/mL)Compound Compound III-1

2.0 57.1 27.0 ++ * III-2

2.4 57.1 27.4 +++ ** III-3

3.6 57.1 8.7 +++ *** III-4

3.6 57.1 16.1 +++ *** III-5

3.4 57.1 25.7 +++ *** III-6

2.0 69.1 23.8 ++ * III-7

3.7 57.1 1.6 +++ ** III-8

3.7 57.1 0.5 + * III-9

2.2 57.1 18.0 +++ ** III-10

2.2 57.1 15.3 +++ ** III-11

2.2 57.1 13.4 +++ ** III-12

1.9 57.1 38.4 + * III-13

3.8 57.1 0.3 +++ *** III-14

4.3 57.1 10.7 ++ ** III-15

2.6 57.1 14.1 +++ *** III-16

2.5 69.4 1.1 +++ ** III-17

2.7 69.4 2.2 + * III-18

2.5 69.4 17.4 +++ ** III-19

2.5 69.4 5.3 + * III-20

2.5 69.4 6.3 +++ * III-21

2.5 69.4 10.0 + * III-22

3.3 60.3 0.5 ++ * III-23

3.3 60.3 6.8 +++ *** III-24

2.3 69.4 8.1 +++ ** III-25

2.3 69.4 22.5 + * III-26

2.1 69.4 26.0 ++ * III-27

2.1 69.4 18.0 + * III-28

2.1 69.4 27.6 ++ * III-29

2.1 69.4 18.9 + * III-30

2.9 60.3 4.7 + * III-31

2.9 60.3 43.5 +++ *** III-32

3.6 57.1 0.1 +++ ** III-33

3.6 57.1 0.5 ++ * III-34

1.7 57.1 10.3 + * III-35

2.4 69.4 6.5 +++ ** III-36

2.4 69.4 0.4 +++ *** III-37

3.8 69.4 2.1 +++ ** III-38

2.6 78.7 18.2 + * III-39

2.8 78.7 4.4 +++ ** III-40

2.4 78.7 20.0 + * III-41

2.9 69.4 1.9 +++ ** III-42

2.5 69.4 15.1 +++ * III-43

1.9 69.4 12.1 ++ * III-44

2.8 69.1 3.0 +++ *** III-45

2.4 57.1 10.2 +++ *** III-46

3.0 66.3 3.4 ++ * III-47

3.4 66.3 0.3 +++ ** III-48

2.9 69.4 19.8 ++ * III-49

2.9 69.4 2.5 +++ * III-50

2.1 69.4 1.6 +++ ** III-51

2.7 69.4 14.1 + * III-52

2.7 69.4 2.4 +++ * III-55

3.4 66.3 1.7 +++ *** III-56

3.7 57.1 1.1 +++ *** III-57

3.6 66.3 2.7 +++ *** III-58

1.5 69.5 20.1 + * III-59

1.9 69.5 10.3 ++ * III-60

2.2 60.3 4.4 ++ * III-61

3.1 60.3 5.5 +++ *** III-62

3.5 69.4 1.2 +++ *** III-63

3.1 69.4 0.2 ++ ** III-64

4.1 57.1 6.2 +++ *** III-65

4.3 57.1 0.9 +++ *** III-66

3.4 60.3 0.3 +++ *** III-67

2.8 60.3 1.9 +++ *** III-68

2.8 57.1 11.9 + * III-69

3.6 66.3 0.5 +++ *** III-70

3.0 80.9 2.1 +++ *** III-71

3.4 80.7 0.5 +++ *** III-72

3.3 80.9 0.1 +++ *** III-73

2.4 100.2 0.4 +++ *** III-74

3.4 66.3 0.8 +++ ** III-75

3.7 57.1 0.6 +++ *** III-76

3.9 66.3 0.2 +++ *** III-77

4.0 66.3 0.3 +++ *** III-78

3.0 69.1 5.6 +++ *** III-79

3.3 75.5 0.5 +++ *** III-80

3.8 57.1 0.2 +++ ** III-81

4.3 57.1 1.5 +++ *** III-82

4.2 66.3 1.5 +++ *** III-83

NA 78.7 0.3 +++ *** III-84

3.7 69.4 0.8 +++ *** III-85

3.6 69.4 1.0 +++ ***

TABLE 3B Compound Com- Solubility in Percent Gcase Activation poundWater 1 μM Test 0.1 μM Test No. Compound Structure cLogP PSA (μg/mL)Compound Compound III-86

N/A N/A 2.8 +++ ** III-87

N/A N/A N/A + * III-88

2.4 69.4 14.8 +++ *** III-89

2.4 69.4 10.4 +++ ** III-90

N/A N/A 2.0 +++ *** III-91

N/A N/A 1.7 +++ *** III-92

N/A N/A 0.2 +++ *** III-93

N/A N/A N/A +++ ** III-94

N/A N/A 0.6 +++ *** III-95

N/A N/A 1.0 +++ *** III-96

3.6 66.3 2.0 +++ *** III-97

N/A N/A 0.2 +++ ** III-98

N/A N/A 0.3 +++ *** III-99

4.3 57.1 0.2 ++ *** III-100

N/A N/A 0.9 +++ *** III-101

N/A N/A 1.3 +++ *** III-102

3.9 72.7 0.4 + * III-103

3.5 91.0 0.8 +++ * III-104

3.1 78.7 0.02 +++ *** III-105

3.5 78.7 0.08 +++ *** III-106

3.1 78.7 0.1 ++ *** III-107

2.8 72.7 0.1 +++ *** III-108

2.8 78.7 0.3 +++ *** III-109

N/A N/A 0.5 +++ *** III-110

N/A N/A 0.4 +++ *** III-111

4.0 57.1 0.07 +++ *** III-112

2.6 69.4 0.8 +++ *** III-113

2.6 69.4 1.0 +++ *** III-114

2.6 69.4 2.1 +++ *** III-115

2.6 69.4 1.9 +++ *** III-116

3.1 69.4 1.0 +++ *** III-117

N/A N/A 0.8 +++ *** III-118

N/A N/A 0.4 +++ *** III-119

3.1 69.4 0.08 +++ *** III-120

3.1 69.4 0.7 +++ *** III-121

3.1 69.4 0.7 +++ *** III-122

2.9 69.4 2.1 +++ *** III-123

2.9 69.4 2.1 +++ ** III-124

2.6 69.4 1.9 +++ *** III-125

2.6 69.4 3.4 +++ *** III-126

2.6 69.4 1.8 +++ *** III-127

2.6 69.4 2.5 +++ *** III-128

3.1 80.9 3.0 +++ *** III-129

3.3 90.1 0.02 +++ *** III-130

2.8 69.4 0.2 +++ *** III-131

3.1 69.4 0.6 +++ *** III-132

N/A N/A N/A +++ ** III-133

2.4 93.2 0.2 +++ ** III-134

2.5 69.4 0.8 +++ ** III-135

N/A N/A 1.5 +++ ** III-136

3.6 57.1 5.1 +++ *** III-137

3.8 66.3 0.8 +++ *** III-138

3.0 66.3 2.5 +++ ** III-139

3.3 66.3 0.1 +++ ** III-140

2.8 66.3 1.1 +++ ** III-141

3.0 90.1 1.1 +++ * III-142

2.5 90.1 2.2 + * III-143

2.7 90.1 17.4 + * III-144

N/A N/A N/A + * III-145

3.6 66.3 0.2 +++ *** III-146

3.2 66.3 0.9 +++ *** III-147

3.9 66.3 0.4 +++ *** III-148

3.4 66.3 1.2 +++ ** III-149

3.5 66.3 1.1 +++ *** III-150

3.1 66.3 0.7 +++ *** III-151

3.4 80.9 0.1 +++ *** III-152

3.1 80.9 0.5 +++ *** III-153

N/A N/A 4.5 +++ ** III-154

3.0 80.9 0.7 +++ *** III-155

N/A N/A N/A ++ * III-156

N/A N/A 0.3 +++ *** III-157

3.1 80.9 2.9 +++ *** III-158

3.4 89 0.3 +++ *** III-159

3.0 80.9 3.8 +++ ** III-160

2.0 100.0 1.1 +++ ** III-161

2.1 112.5 1.0 +++ * III-162

2.3 100.0 1.0 +++ *** III-163

4.0 57.1 0.4 +++ *** III-164

3.5 57.1 1.1 +++ *** III-165

2.4 69.1 4.0 +++ ** III-166

2.6 69.1 10.9 +++ ** III-167

2.6 78.7 0.7 +++ *** III-168

2.6 78.7 0.3 +++ *** III-169

2.6 78.7 1.6 +++ *** III-170

2.3 72.7 0.5 ++ ** III-171

3.1 78.7 0.4 +++ *** III-172

2.2 72.7 0.5 +++ *** III-173

N/A N/A 1.4 +++ *** III-174

N/A N/A N/A +++ *** III-175

2.5 94.1 1.0 + * III-176

3.3 91.0 0.2 +++ *** III-177

2.5 94.1 0.2 +++ *** III-178

2.4 69.4 0.7 +++ ** III-179

3.0 60.3 1.1 +++ *** III-180

2.4 60.3 4.8 +++ ** III-181

2.1 60.3 4.5 +++ * III-182

3.6 75.5 0.2 ++ *** III-183

3.9 75.5 0.5 +++ *** III-184

3.6 57.1 1.1 +++ *** III-185

2.6 90.1 6.3 +++ *** III-186

3.2 66.3 0.6 +++ *** III-187

3.0 66.3 0.5 +++ *** III-188

3.0 80.9 0.3 +++ *** III-189

3.2 80.9 5.1 +++ *** III-190

2.4 66.3 8.9 + * III-191

2.7 66.3 26.3 +++ * III-192

3.5 69.4 0.2 +++ *** III-193

N/A N/A N/A +++ *** III-194

3.0 66.7 0.4 +++ *** III-195

N/A N/A 0.01 +++ *** III-196

N/A N/A N/A +++ *** III-197

2.5 69.4 6.5 +++ *** III-198

N/A N/A N/A +++ * III-199

2.1 69.4 7.8 ++ * III-200

2.7 69.4 1.0 +++ *** III-201

N/A N/A 3.1 +++ *** III-202

N/A N/A 2.5 +++ *** III-203

2.8 69.4 0.07 +++ *** III-204

2.8 69.4 0.1 +++ *** III-205

2.8 69.4 0.1 +++ *** III-206

3.1 69.4 2.1 +++ *** III-207

3.4 69.4 0.6 +++ *** III-208

3.4 69.4 0.04 + ** III-209

2.4 69.4 1.2 +++ *** III-210

3.6 75.5 2.4 +++ *** III-211

3.3 80.9 0.2 +++ *** III-212

3.3 80.9 0.7 ++ * III-213

3.3 80.9 0.6 +++ *** III-214

3.3 69.4 2.3 +++ *** III-215

N/A N/A 0.3 +++ *** III-216

N/A N/A 0.9 +++ *** III-217

2.8 78.7 3.2 +++ ** III-218

N/A N/A N/A ++ * III-219

3.0 78.7 2.7 ++ ** III-220

3.3 69.4 0.1 +++ *** III-221

3.3 69.4 0.2 +++ *** III-222

3.5 69.4 0.6 +++ *** III-223

3.2 78.7 0.2 +++ *** III-224

2.6 80.6 1.2 +++ ** III-225

2.1 80.6 19.3 +++ ** III-226

2.2 80.6 5.9 ++ * III-227

1.6 80.6 9.4 + * III-228

2.1 89.4 2.4 +++ * III-229

2.3 80.6 13.5 ++ * III-230

2.2 80.6 2.6 ++ * III-231

2.0 80.6 3.0 ++ * III-232

1.8 80.6 23.7 + * III-233

1.5 80.6 0.7 +++ ** III-234

2.9 69.4 0.2 +++ *** III-235

N/A N/A 6.4 +++ ** III-236

N/A N/A 5.9 +++ *** III-237

3.4 69.4 0.05 +++ *** III-238

2.3 69.5 13.5 +++ * III-239

2.1 78.7 0.8 +++ ** III-240

N/A N/A N/A +++ *** III-241

N/A N/A N/A +++ *** III-242

2.6 90.1 3.2 +++ *** III-243

N/A N/A N/A +++ *** III-244

N/A N/A N/A +++ *** III-245

3.1 90.1 0.008 + * III-246

2.0 78.7 3.1 +++ ** III-247

N/A N/A 0.6 +++ *** III-248

N/A N/A 0.7 +++ *** III-249

2.0 78.7 0.6 +++ ** III-250

2.6 90.1 0.4 +++ *** III-251

2.2 78.7 3.9 +++ ** III-252

2.2 78.7 11.0 +++ * III-253

2.0 78.7 0.7 +++ *** III-254

2.0 78.7 0.6 +++ *** III-255

N/A N/A 1.6 +++ ** III-256

N/A N/A 0.5 +++ *** III-257

2.6 80.6 11.6 ++ ** III-258

2.3 80.6 26.4 + * III-259

2.2 80.6 25.8 + * III-260

2.1 80.6 21.0 ++ * III-261

2.8 80.6 23.0 + * III-262

2.5 80.6 19.0 + * III-263

2.2 78.7 8.9 ++ * III-264

3.3 66.3 0.4 +++ *** III-265

2.8 78.7 1.3 +++ *** III-266

N/A N/A N/A +++ *** III-267

N/A N/A N/A +++ *** III-268

3.2 78.7 1.2 +++ *** III-269

1.8 78.7 12.7 + * III-270

2.4 78.7 4.9 +++ ** III-271

2.8 78.7 2.3 +++ *** III-272

N/A N/A 3.1 +++ ** III-273

N/A N/A 3.4 +++ *** III-274

2.1 69.4 2.3 +++ * III-275

2.9 69.4 2.6 +++ *** III-276

N/A N/A 1.8 +++ *** III-277

N/A N/A 5.3 +++ *** III-278

2.9 69.4 0.5 +++ *** III-279

N/A N/A 1.5 +++ ** III-280

N/A N/A 1.3 +++ *** III-281

2.1 69.4 12.5 + * III-282

2.4 69.4 6.2 +++ ** III-283

2.4 69.4 12.7 ++ * III-284

2.9 69.4 13.2 +++ ** III-285

2.9 69.4 1.2 +++ *** III-286

N/A N/A 2.1 +++ *** III-287

N/A N/A 2.4 +++ *** III-288

2.9 69.4 1.4 +++ ** III-289

3.4 75.5 0.8 +++ *** III-290

2.9 69.4 2.1 +++ *** III-291

N/A N/A N/A +++ *** III-292

3.3 69.4 0.3 +++ *** III-293

3.7 78.7 0.3 +++ *** III-294

3.6 75.5 0.6 +++ *** III-295

2.9 78.7 3.4 +++ *** III-296

2.9 78.7 N/A +++ *** III-297

2.9 78.7 N/A +++ *** III-298

3.3 75.5 1.5 +++ *** III-299

3.2 69.5 0.5 +++ *** III-300

2.8 80.9 1.4 +++ *** III-301

3.0 80.9 1.1 +++ *** III-302

N/A N/A 0.5 +++ *** III-303

3.3 72.7 3.2 + ** III-304

3.3 72.7 0.4 +++ ** III-305

N/A N/A N/A +++ *** III-306

N/A N/A N/A +++ *** III-307

3.2 81.5 0.3 ++ *** III-308

3.2 81.5 4.6 +++ * III-309

3.3 72.7 31.4 + * III-310

3.3 72.7 0.3 +++ ** III-311

3.6 81.5 0.6 ++ * III-312

3.5 72.7 0.3 ++ ** III-313

3.4 86.6 0.1 +++ *** III-314

2.3 86.6 0.2 +++ *** III-315

2.3 86.6 0.1 +++ *** III-316

2.2 86.6 1.3 +++ ** III-317

2.2 86.6 N/A +++ ** III-318

2.2 86.6 N/A +++ ** III-319

3.1 89.4 1.3 +++ ** III-320

3.5 89.4 N/A +++ *** III-321

3.1 78.7 1.9 +++ *** III-322

3.1 66.3 N/A +++ *** III-323

3.1 66.3 N/A +++ ** III-324

1.4 81.8 N/A + * III-325

1.2 81.8 14.6 + * III-326

2.1 80.6 21.0 +++ * III-327

2.1 80.6 32.8 +++ ** III-328

2.7 77.4 3.3 +++ ** III-329

2.3 80.6 N/A + * III-330

2.7 80.6 N/A ++ ** III-331

2.3 78.7 1.0 +++ *** III-332

2.5 78.7 N/A +++ *** III-333

2.0 78.7 N/A +++ *** III-334

2.9 66.3 2.0 +++ *** III-335

2.7 66.3 N/A +++ *** III-336

2.8 66.3 N/A +++ *** III-337

2.6 66.3 N/A +++ *** III-338

3.1 66.3 0.2 +++ *** III-339

3.1 66.3 N/A +++ *** III-340

3.1 66.3 N/A +++ *** III-341

2.4 78.7 N/A +++ *** III-342

2.1 78.7 N/A +++ *** III-343

2.4 78.7 1.5 +++ *** III-344

2.1 78.7 N/A +++ *** III-345

1.8 78.5 1.0 +++ ** III-346

3.0 69.4 18.8 +++ ** III-347

3.3 80.9 N/A +++ *** III-348

3.3 80.9 N/A +++ *** III-349

3.0 80.9 0.1 ++ *** III-350

3.0 80.9 0.3 +++ *** III-351

3.0 90.9 N/A +++ ** III-352

3.0 90.9 N/A +++ ** III-353

3.4 69.4 8.3 +++ *** III-354

3.4 69.4 13.5 +++ *** III-355

3.4 69.4 0.1 +++ *** III-356

3.4 69.4 N/A +++ *** III-357

2.3 80.6 N/A +++ ** III-358

1.8 86.6 N/A ++ * III-359

3.5 57.1 0.7 +++ ** III-360

3.5 57.1 0.7 +++ *** III-361

3.5 57.1 0.7 +++ *** III-362

3.5 57.1 0.6 +++ *** III-363

2.0 93.2 1.7 +++ *** III-364

2.0 93.2 N/A +++ ** III-365

2.2 93.2 1.8 +++ ** III-366

2.2 93.2 1.1 +++ *** III-367

2.2 93.2 0.4 +++ ** III-368

2.2 93.2 N/A +++ ** III-369

2.1 93.2 N/A +++ ** III-370

2.3 93.2 N/A +++ * III-371

2.3 93.2 N/A +++ * III-372

3.1 69.4 1.7 +++ *** III-373

3.1 69.4 N/A +++ *** III-374

3.1 69.4 1.1 +++ *** III-375

3.1 69.4 N/A +++ *** III-376

2.6 69.4 N/A + * III-377

2.6 69.4 N/A + * III-378

2.8 69.4 N/A +++ ** III-379

2.8 69.4 N/A +++ ** III-380

3.1 69.4 0.3 +++ *** III-381

3.1 69.4 N/A +++ *** III-382

3.1 69.4 N/A +++ *** III-383

2.6 69.4 0.2 +++ *** III-384

2.9 87.9 0.1 +++ ** III-385

3.0 69.4 N/A + * III-386

3.0 69.4 N/A + * III-387

2.8 69.4 N/A +++ *** III-388

2.8 69.4 N/A +++ *** III-389

2.8 69.4 N/A +++ *** III-390

2.8 69.4 N/A +++ *** III-391

2.5 91.0 0.3 +++ ** III-392

2.5 91.0 0.4 +++ ** III-393

2.6 91.0 N/A +++ *** III-394

2.6 91.0 0.7 +++ *** III-395

1.5 80.9 N/A ++ * III-396

3.1 80.9 0.3 +++ *** III-397

3.1 80.9 N/A +++ ** III-398

3.1 80.9 0.2 +++ *** III-399

3.0 80.9 0.1 +++ *** III-400

3.0 80.9 N/A +++ ** III-401

2.2 91.0 N/A +++ *** III-402

2.3 91.0 N/A +++ *** III-403

2.7 66.3 21.4 ++ * III-404

2.7 66.3 15.1 +++ * III-405

3.7 66.3 1.5 +++ *** III-406

4.3 57.1 0.8 +++ *** III-407

3.0 69.4 0.09 + * III-408

2.5 69.4 0.4 +++ ** III-409

3.6 66.3 0.9 +++ *** III-410

3.6 66.3 0.06 +++ *** III-411

2.8 69.4 0.7 +++ *** III-412

2.6 69.4 3.7 +++ * III-413

2.3 77.4 6.0 +++ * III-414

2.7 86.2 1.6 +++ * III-415

3.9 72.7 1.2 ++ *** III-416

3.6 78.7 0.3 +++ *** III-417

3.5 81.8 0.04 +++ ***

TABLE 4 Compound Solubility in Percent Gcase Activation Compound Water 1μM Test 0.1 μM Test No. Compound Structure cLogP PSA (μg/mL) CompoundCompound IV-1

2.2 57.1 <1.5 ++ ** IV-2

2.5 60.3 5.1 + * IV-3

3.0 60.3 <1.5 + * IV-4

1.7 75.5 0.6 ++ * IV-5

3.1 57.1 0.5 +++ **

INCORPORATION BY REFERENCE

The entire disclosure of each of the patent documents and scientificarticles referred to herein is incorporated by reference for allpurposes.

EQUIVALENTS

The invention may be embodied in other specific forms without departingfrom the spirit or essential characteristics thereof. The foregoingembodiments are therefore to be considered in all respects illustrativerather than limiting the invention described herein. Scope of theinvention is thus indicated by the appended claims rather than by theforegoing description, and all changes that come within the meaning andrange of equivalency of the claims are intended to be embraced therein.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: R¹ representsindependently for each occurrence C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄alkoxyl, cyclopropyl, cyano, chloro, or fluoro; R² is hydrogen; R³represents independently for each occurrence hydrogen, C₁₋₆ alkyl, orC₃₋₆ cycloalkyl; R⁴ represents independently for each occurrencehydrogen, C₁₋₄ alkyl, cyclopropyl, or —C(O)R³; R⁷ representsindependently for each occurrence halogen, hydroxyl, cyano, C₁₋₄ alkyl,C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₁₋₄ haloalkoxyl, C₃₋₆ cycloalkyl,—O—(C₃₋₆ cycloalkyl), —O—(C₁₋₆ alkylene)-C₁₋₆ alkoxyl, —(C₁₋₆alkylene)-CN, —N(R⁴)₂, —C(O)N(R⁴)₂, or heteroaryl; R⁸ is a bond or C₁₋₆alkylene; R⁹ is hydrogen or C₁₋₆ alkyl; X¹-A¹ is one of the following:X¹ is —C(O)N(H)(C₁₋₆ haloalkylene)-ψ, where ψ is a bond to A¹; whereinA¹ is one of the following: (i) a 3-14 membered saturated carbocyclylsubstituted by 0, 1, or 2 occurrences of Y¹ and 0, 1, 2, or 3occurrences of Y²; or (ii) C₁₋₈ alkyl; or X¹ is —C(O)N(H)C(C₁₋₆alkyl)₂-R⁸-ψ or —C(O)N(H)C(C₁₋₆ alkyl)(R⁹)—R⁸-ψ, where ψ is a bond toA¹, and A¹ is a 3-5 membered saturated carbocyclyl substituted by 0, 1,or 2 occurrences of Y¹ and 0, 1, 2, or 3 occurrences of Y²; A² is one ofthe following: phenyl substituted by 1, 2, or 3 occurrences of R⁷; or acyclic group selected from a 3-12 membered heterocyclyl, 4-12 memberedoxoheterocyclyl, or 4-10 membered cycloalkyl; each of which isoptionally substituted by 1, 2, or 3 occurrences of R⁷; Y¹ represents,independently for each occurrence, —O—(C₁₋₇ alkyl); Y² represents,independently for each occurrence, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, halogen,C₁₋₆ haloalkyl, C₁₋₆ hydroxyalkyl, or hydroxyl; and n is 1; wherein A²is located at the 5-position of the pyrazolo[1,5-a]pyrimidinyl, and theR¹ group is located at the 7-position of the pyrazolo[1,5-a]pyrimidinyl.2. The compound of claim 1, wherein X¹ is —C(O)N(H)C(H)(CF₃)-ψ.
 3. Thecompound of claim 1, wherein X¹ is —C(O)N(H)C(H)(CF₃)-ψ, and A¹ is C₁₋₈alkyl.
 4. The compound of claim 1, wherein X¹ is —C(O)N(H)(C(H)(CH₃))-ψ.5. The compound of claim 1, wherein A¹ is (i) 3-5 membered saturatedcarbocyclyl, or (ii) a 6-14 membered saturated spirocyclic carbocyclyl,each optionally substituted with 1 or 2 C₁₋₄ alkyl groups.
 6. Thecompound of claim 1, wherein A² is phenyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,hydroxyl, and —N(R⁴)₂.
 7. The compound of claim 3, wherein A² is phenylsubstituted by C₁₋₄ alkoxyl, cyano, or halogen.
 8. The compound of claim2, wherein A² is pyridinyl optionally substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,hydroxyl, and —N(R⁴)₂.
 9. A compound represented by Formula I-A:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is methyl; R²is hydrogen; X¹ is —C(O)N(H)C(H)(CF₃)-ψ, —C(O)N(H)(C(CH₃)₂)-ψ, or—C(O)N(H)(C(H)(CH₃))-ψ, where ψ is a bond to A¹; A¹ is cyclopropyl; andA² is a cyclic group selected from: phenyl substituted by 1, 2, or 3substituents independently selected from the group consisting of C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano, halogen,and hydroxyl; and 5-6 membered heteroaryl optionally substituted by 1,2, or 3 substituents independently selected from the group consisting ofC₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl, cyano,halogen, and hydroxyl.
 10. The compound of claim 9, wherein A² is phenylsubstituted by 1, 2, or 3 substituents independently selected from thegroup consisting of C₁₋₄ haloalkyl, C₁₋₄ alkoxyl, C₃₋₅ cycloalkyl,cyano, and halogen.
 11. The compound of claim 9, wherein A² is pyridinyloptionally substituted by 1, 2, or 3 substituents independently selectedfrom the group consisting of C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxyl,C₃₋₅ cycloalkyl, cyano, halogen, and hydroxyl.
 12. The compound of claim10, wherein X¹ is —C(O)N(H)(C(H)(CH₃))-ψ.
 13. The compound of claim 11,wherein X¹ is —C(O)N(H)C(H)(CF₃)-ψ.
 14. The compound of claim 9, whereinthe compound is

or a pharmaceutically acceptable salt thereof.
 15. The compound of claim9, wherein the compound is

or a pharmaceutically acceptable salt thereof.
 16. The compound of claim15, wherein the compound is


17. A compound having the following formula or a pharmaceuticallyacceptable salt thereof:


18. The compound of claim 17, wherein the compound is


19. A compound having the following formula or a pharmaceuticallyacceptable salt thereof:


20. The compound of claim 19, wherein the compound is


21. A pharmaceutical composition, comprising a compound of claim 1 and apharmaceutically acceptable carrier.
 22. A pharmaceutical composition,comprising a compound of claim 9 and a pharmaceutically acceptablecarrier.
 23. A pharmaceutical composition, comprising a compound ofclaim 14 and a pharmaceutically acceptable carrier.
 24. A pharmaceuticalcomposition, comprising a compound of claim 15 and a pharmaceuticallyacceptable carrier.
 25. A pharmaceutical composition, comprising acompound of claim 16 and a pharmaceutically acceptable carrier.
 26. Apharmaceutical composition, comprising a compound of claim 17 and apharmaceutically acceptable carrier.
 27. A pharmaceutical composition,comprising a compound of claim 18 and a pharmaceutically acceptablecarrier.
 28. A pharmaceutical composition, comprising a compound ofclaim 19 and a pharmaceutically acceptable carrier.
 29. A pharmaceuticalcomposition, comprising a compound of claim 20 and a pharmaceuticallyacceptable carrier.
 30. A method of treating a disorder selected fromthe group consisting of Gaucher disease, Parkinson's disease, Lewy bodydisease, dementia, multiple system atrophy, epilepsy, bipolar disorder,schizophrenia, an anxiety disorder, major depression, polycystic kidneydisease, type 2 diabetes, open angle glaucoma, multiple sclerosis,endometriosis, and multiple myeloma, comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof claim 1 to treat the disorder.